Why do we still use adenoviral type 5 backbones for Gene Therapy?

I worked for several years in adenoviral research. My main research focus was to understand the evolution of adenoviruses and to understand how recombination events of adenoviruses effects the emergence of new adenoviruses. Adenoviruses are widely known as THE gene vector for gene therapy. For example, in HIV clinical vaccination trials (September 2007, STEP trial) human adenovirus Type 5 was used as a vector for a vaccine (HIV-1 gag/pol/nef) from Merck & Co Inc, but it was halted at the first interim analysis because the vaccine demonstrated no positive impact on virus acquisition or virus load following infection (see a comprehensive review here: Bradac et al.)

I want to share some thoughts and ideas in the following paragraphs on  C5 backbone gene therapy vectors:

It is well known that Loop1 and Loop2 of the adenoviral hexon gene is responsible for antibody binding and for subsequently neutralizing the adenovirus. Most vectors today are based on an adenoviral Type 5 (species C) backbone. The obvious problem is that most humans have antibodies against this type as there is a high probability of becoming infected with a wild type C5 in a lifetime. Loop1 and Loop2 - located in the hexon gene - are very important for the structure of human adenoviruses. However, knocking these genes out is also not a solution. In my opinion, it is not understandable why Merck is starting a large trial with a virus as a backbone (Type 5 species C), where the probability is relatively high that the vaccine will be destroyed by preformed antibodies.

Just recently a PNAS paper demonstrated the following:"This suggests that adenoviral-based vaccination against HIV-1 in individuals with pre-existing immunity against Ad5 results in preferential expansion of HIV-susceptible activated CD4 T cells that home to mucosal tissues, increases the number of virus targets, and leads to a higher susceptibility to HIV acquisition." This paper is extensive and it underlines my findings.

I suggested in my papers (this and this) published in Journal of Virology in 2005  and 2007  that we should use adenoviral vector therapy backbones from either bovine adenoviruses or adenoviruses from species D, or at least swap the hexon gene.

I also demonstrated in my research (Analysis of a unique adenoviral prime strain, p'17H30, Madisch et al.) that our immune systems are building antibodies against the penton protein and fiber gene, which may also affect the efficiency of an adenoviral vector. I recently co-authored a paper published in PLoS One, where we detected a new adenoviral type: This type was interesting because the backbone of the adenovirus does not usually induce disease, but this virus recombinated in a specific way and the virus acquired a pathogen. This virus was "created" by nature and we should look more closely at these naturally occuring recombinated adenoviruses, which give us bold insights into how we should structure adenoviral vectors for gene therapy.

As a conclusion, I want to make the point that we have to move away from the adenoviral 5 backbones to other backbones or swap the antibody neutralization determinants.