Final Report Summary - SHEV (Stabilizing the exposure of neutralization epitopes on HIV-1 envelope glycoprotein trimer vaccines)
The impact of HIV/AIDS on world healthcare is tremendous, particularly in the Third World. To curtail the HIV epidemic a cheap and effective vaccine is urgently needed, but despite massive research efforts no vaccine is available yet. Although most vaccines work by inducing neutralizing antibodies, HIV has evolved many ways to limit the induction and binding of neutralizing antibodies. The lack of effective HIV-1 envelope glycoprotein (Env) subunit vaccines, despite decades of research, also illustrates our poor understanding of protein immunogenicity in general and our inability to manipulate protein immunogenicity. The challenge is to engineer Env subunit vaccines that do induce neutralizing antibodies efficiently. Many reasons underlie the resistance of HIV Env to the induction and binding of neutralizing antibodies. For example, conserved neutralization epitopes are shielded by variable domains and sugars. One aspect that has been highly underappreciated is instability and conformational heterogeneity of Env. Instability and flexibility provide very unstable targets for recognition by low affinity B cell receptors on naïve B cells, diminishing the chance of efficient B cell receptor cross-linking, efficient B cell activation, antibody affinity maturation and the secretion of neutralizing antibodies.
Using a number of novel structure-based vaccine design strategies that included the introduction of stabilizing disulfide bonds, strengthening hydrophobic interactions and otehrs, we tackled these instability and flexibility problems. We developed highly stable mimics of the native Env trimer, termed SOSIP trimers. The prototype, BG505 SOSIP.664 induced neutralizing antibodies against the neutralization-resistant (Tier-2) parental virus isolate in rabbits and macaques, something that had not been previously achieved by previous HIV vaccines. The protein is currently being made under clinical-grade GMP conditions for testing clinical trials in human. The first human trial is scheduled to start at the end of 2017. Moreover, the BG505 SOSIP.664 protein yielded the first high-resolution structures of the Env trimer, allowing for structure based vaccine design. For these reasons, SOSIP trimers now form the platform for many worldwide HIV vaccine approaches aimed at inducing neutralizing antibodies.
Over the course of the project we have published over a 100 papers describing our work in leading journals such as Science, Nature, Cell and others. These papers have attracted thousands of citations. In consequence, the PI shared the top position in a top-10 list of “hottest authors” in HIV/AIDS research 2013-2015, compiled by Thomson Reuters, and as a consequence the ERC was in the top list of institutions funding "hot" HIV research (http://stateofinnovation.thomsonreuters.com/hivaids-research-transforms-outcome-of-disease). Unfortunately, these achievements did not result in continued funding from the ERC in the form of an ERC Consolidator Grant.
Using a number of novel structure-based vaccine design strategies that included the introduction of stabilizing disulfide bonds, strengthening hydrophobic interactions and otehrs, we tackled these instability and flexibility problems. We developed highly stable mimics of the native Env trimer, termed SOSIP trimers. The prototype, BG505 SOSIP.664 induced neutralizing antibodies against the neutralization-resistant (Tier-2) parental virus isolate in rabbits and macaques, something that had not been previously achieved by previous HIV vaccines. The protein is currently being made under clinical-grade GMP conditions for testing clinical trials in human. The first human trial is scheduled to start at the end of 2017. Moreover, the BG505 SOSIP.664 protein yielded the first high-resolution structures of the Env trimer, allowing for structure based vaccine design. For these reasons, SOSIP trimers now form the platform for many worldwide HIV vaccine approaches aimed at inducing neutralizing antibodies.
Over the course of the project we have published over a 100 papers describing our work in leading journals such as Science, Nature, Cell and others. These papers have attracted thousands of citations. In consequence, the PI shared the top position in a top-10 list of “hottest authors” in HIV/AIDS research 2013-2015, compiled by Thomson Reuters, and as a consequence the ERC was in the top list of institutions funding "hot" HIV research (http://stateofinnovation.thomsonreuters.com/hivaids-research-transforms-outcome-of-disease). Unfortunately, these achievements did not result in continued funding from the ERC in the form of an ERC Consolidator Grant.