Bethesda / Boston - In the USA, clinical studies with broadly effective antibodies that are supposed to protect against infection with the HI virus will soon begin. Preparatory animal studies in Science Translational Medicine (2017; 9: eaao4235) show that several antibodies probably have to be combined to prevent infection. In Science (2017; doi: 10.1126 / science.aan8630) researchers present synthetic antibody that recognizes three antigens of the HI virus.
The sexual transmission of HIV does not take place with individual genetic viruses. Rather, the immune system is confronted with “swarm” of different HIV variants against which it cannot build up immune protection. For this reason, the previous vaccines have also failed.
Therefore, the international no longer relies on single vaccine, but on combinations. There is also less experimentation at present with vaccines for active immunization, in which the immune system produces the protective antibodies after contact with an antigen. Rather, the focus is on passive immunization, in which the protective antibodies are infused into the body.
The reason for the change of heart was the discovery of broadly effective antibodies. They recognize components of the virus envelope that are not changed, otherwise the ability to infect would be lost.
In preparation for clinical study, team led by Dan Barouch from the Beth Israel Deaconess Medical Center in Boston tested the antibodies PGT121 and PGDM1400 tested on rhesus monkeys. Both are among the broadly effective antibodies that recognize the vast majority of known HIV variants. As monotherapy, however, neither vaccine was able to protect the monkeys from infection with the simian human immunodeficiency virus (SHIV). However, if both antibodies were administered together, neither of the animals fell ill after deliberately infected with SHIV, which corresponds to the HIV virus in humans.
These results justify the hope that one of the two planned clinical studies will be used of broad-acting antibodies will be successful. In the study, 60 people with an increased risk of infection will be treated either with the antibody PGDM1400 or with combination of the antibodies PGDM1400 and PGT121 (NCT03205917). In the second study only the use of the antibody PGT121 is planned (NCT02960581). According to the latest results from Barouch, the question arises whether this study is still useful.
Another step forward could be the development of trispecific antibodies, which researchers at the Sanofi company in Paris have succeeded in doing . Usually antibodies have only two binding sites for antigens. Using chemical process that the manufacturer calls “button-in-hole heterodimerization”, two binding sites could be placed on one arm of the y-shaped antibody.
In first step, different trispecific antibodies were created tested in the laboratory for their ability to neutralize HIV viruses. The best results were achieved with an antibody that combines the binding sites of the broadly active antibodies VRC01, PGDM1400 and 10E8v4.
Thereafter, three groups of eight monkeys each received infusions with the antibodies VRC01, PGDM1400 or the trispecific antibody. Five days later, all monkeys were inoculated with SHIV. Five of the eight monkeys who received PGDM1400 and six of the eight monkeys who received VRC01 became infected, while the trispecific antibodies successfully repelled the virus in all eight animals. In the next step, clinical phase 1 study is planned, which will initially examine the safety of the antibody in healthy volunteers. Studies on people with an increased risk of infection could then follow later.