Development of highly neutralizing nanobodies against HIV-1, SARS-CoV-2 and other pathogens

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

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Abstract

HIV-1 and -2 are lentiviruses that cause acquired immunodeficiency syndrome (AIDS) in humans. To date, no effective vaccine has been developed and according to the World Health Organization nearly 40 million people are infected with HIV across the world. Because preventive measures and treatments are not widely available, AIDS is the leading cause of death in areas such as Sub-Saharan Africa. There is therefore an urgent need to develop efficient methods, including vaccines and immunotherapies, to prevent HIV infection in susceptible populations. A near-native trimer mimic, BG505 DS-SOSIP, has been shown to be a nice immunogen for HIV-1 vaccination in various animal models. Here we injected this immunogen in llama to develop heavy chain-only antibodies, aiming to generate broad and potent neutralizing nanobodies (bNNABs) against HIV-1. Two nanobodies that we identified through phage screening, mT36 and R27, when engineered in trimeric form, can neutralize a panel of 20 HIV-1 strains from various clades. We are currently testing their activity on a 208-strain panel. Epitope mapping and structural analysis will reveal their neutralization mechanism and provide essential information that can guide the optimization of the immunogen. Nanobodys unique properties such as low-cost, high-yield production and great stability will make bNNbs ideal therapeutics for controlling the long-lasting AIDS pandemic. The HMPV surface glycoprotein F mediates the fusion of viral and cellular membrane and is an attractive target for hMPV vaccine and neutralizing antibodies development. This fiscal year, we immunized llama with the third generation prefusion stabilized F protein developed at VRC/NIH, and isolated dozens of nanobodies targeting different epitopes on F protein. The neutralization activity of these nanobodies is currently under investigation. Structural analysis of both neutralizing and non-neutralizing nanobodies will likely assist the further refinement of F immunogen. And we expect that engineering such as Fc conjugation and multimerization can lead to a potent nanobody/antibody therapeutic for hMPV infection.