Robert Koch Award 2016, together with Alberto Mantovani
Michel C. Nussenzweig’s groundbreaking work uncovered broad and potent neutralizing antibodies to HIV-1 and established that they are a safe and effective immunotherapeutic for infected humans. Nussenzweig addressed a fundamental issue in immunology – the lack of a detailed understanding of the human antibody response – by developing robust and scalable methods for the cloning of antibody genes from single human B cells. He first applied this approach to define how tolerance develops in normal individuals and later to the HIV-1 antibody problem.
Antibodies that neutralize HIV-1 were first isolated early in the epidemic. Although these antibodies protected macaques from infection, the doses were so high that it led the field to abandon antibody-based vaccines and therapies. Nussenzweig’s discoveries of potent anti-HIV antibodies have re-energized the vaccine field and opened the door to new antibody based methods for HIV-1 prevention and therapy.
Nussenzweig made the key breakthrough in this area by applying his antibody cloning techniques to anti-HIV antibodies. His work, and that of others that rapidly adopted his methods, led to the discovery of naturally arising anti-HIV antibodies that were orders of magnitude more potent than previously known antibodies. Moreover, they revealed novel targets of vulnerability. The new antibodies neutralized up to 95% of all HIV-1 strains individually, and nearly all known strains when combined even at very low concentrations.
The antibody cloning experiments revealed that anti-HIV-1 antibodies differ from antibodies to nearly all other pathogens in their high rate of somatic mutation. This observation led Nussenzweig to propose the idea that these antibodies arise by sequential, iterative rounds of antibody mutation, selection, and viral escape. Nussenzweig went on to establish that sequential immunization can elicit such antibodies in mouse models and his ideas are the basis for new vaccination trials in humans.
In addition to his work on vaccines, Nussenzweig established that passive administration of the antibodies he cloned can control infection in humanized mice and in macaques chronically infected with SHIV. Moreover, he showed that a single antibody injection can protect macaques from SHIV infection for up to 23 weeks and he established a relationship between antibody concentration in serum and protective activity.
The results obtained in Nussenzweig’s pre-clinical studies led him to conduct phase 1 clinical trials in HIV-1 infected individuals. His groundbreaking studies in humans established that antibodies are safe and effective for HIV-1 prevention and therapy in humans. A single infusion of one of his antibodies, 3BNC117, was well-tolerated, rapidly decreased viral loads in viremic individuals by an average of 1.48 logs, and this effect remained significant for 4 weeks. In addition, the antibody infusions activated endogenous host immune responses against the virus, and accelerated the clearance of virus and infected cells.
Based on his results Nussenzweig proposed that antibodies might be administered on a quarterly or bi-annual basis for therapy or passive protection in humans. Clinical trials to test this idea are currently underway.