Passively transferred neutralizing antibodies (nAbs) have provided definitive protection from HIV-1 infection, yet identification and mechanistic study of these nAbs has not resulted in the development of a protective vaccine. We hypothesize that previous immunogen design efforts have achieved limited success due to their limited scope and restricted focus. The lack of a high-performance screening platform places severe constraints on immunogen design and has impeded the translation of findings from basic science into vaccine development. When attempting to elicit protective antibodies against a highly diverse virus in the context of a disease in which naturally occurring protective immune responses are largely absent, we posit that the scale of technology and methods used must be adequately matched to the scale of the task. Combinatorial, high-throughput protein engineering platforms can achieve the landscape coverage that may be necessary for successful development of a preventative HIV vaccine, and allow us to translate our understanding of nAbs into the induction of protective antibody responses. We therefore propose to develop high-performance protein engineering tools to screen billions of HIV envelope trimer sequence variants according to defined criteria, allowing us to evolve envelope immunogens tailored to effectively present functionally relevant and immunogenic epitopes capable of driving the generation of protective antibodies. The multi-pronged strategy we describe both leverages the growing reagent toolkit for traditional immunogen design, including more than a dozen new broad nAbs, and improved means to functionally parse Abs present in diverse, polyclonal samples;and further explores a complementary strategy based on selective engagement of na?ve and germline antibody repertoires which we believe addresses the fundamental limitation of previous immunogen design efforts and represents an innovative and unbiased forward engineering strategy to induce the generation of neutralizing antibodies. Ultimately, the tools developed by these studies represent adaptable platforms capable of rapidly selecting envelope variants from vast sequence diversity according to flexible design criteria, and may open a path to a fundamental breakthrough in immunogen design by bridging the translational gap that has come to be known as """"""""the nAb problem"""""""".

Public Health Relevance

Our proposed studies aim to improve our understanding of the interaction between the HIV envelope and the immune system, providing new insight into envelope-based vaccine design, facilitating development of a protective vaccine to contain the HIV epidemic.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-DR-A (M1))
Program Officer
Onami, Thandi M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dartmouth College
Schools of Engineering
United States
Zip Code
Hua, Casey K; Ackerman, Margaret E (2016) Engineering broadly neutralizing antibodies for HIV prevention and therapy. Adv Drug Deliv Rev 103:157-73
Chan, Ying N; Boesch, Austin W; Osei-Owusu, Nana Y et al. (2016) IgG Binding Characteristics of Rhesus Macaque FcγR. J Immunol 197:2936-47
Ackerman, Margaret E; Mikhailova, Anastassia; Brown, Eric P et al. (2016) Polyfunctional HIV-Specific Antibody Responses Are Associated with Spontaneous HIV Control. PLoS Pathog 12:e1005315
Huang, Yunda; Ferrari, Guido; Alter, Galit et al. (2016) Diversity of Antiviral IgG Effector Activities Observed in HIV-Infected and Vaccinated Subjects. J Immunol 197:4603-4612
Boesch, Austin W; Alter, Galit; Ackerman, Margaret E (2015) Prospects for engineering HIV-specific antibodies for enhanced effector function and half-life. Curr Opin HIV AIDS 10:160-9
Brown, Eric P; Normandin, Erica; Osei-Owusu, Nana Yaw et al. (2015) Microscale purification of antigen-specific antibodies. J Immunol Methods 425:27-36
Grimm, Sebastian K; Battles, Michael B; Ackerman, Margaret E (2015) Directed evolution of a yeast-displayed HIV-1 SOSIP gp140 spike protein toward improved expression and affinity for conformational antibodies. PLoS One 10:e0117227
Barouch, Dan H; Alter, Galit; Broge, Thomas et al. (2015) Protective efficacy of adenovirus/protein vaccines against SIV challenges in rhesus monkeys. Science 349:320-4
Boesch, Austin W; Brown, Eric P; Ackerman, Margaret E (2015) The role of Fc receptors in HIV prevention and therapy. Immunol Rev 268:296-310
Bonsignori, Mattia; Wiehe, Kevin; Grimm, Sebastian K et al. (2014) An autoreactive antibody from an SLE/HIV-1 individual broadly neutralizes HIV-1. J Clin Invest 124:1835-43

Showing the most recent 10 out of 14 publications