Effective HIV vaccine: narrow path to broadly neutralizing antibodies?

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The quest for a prophylactic vaccine against the human immunodeficiency virus is almost as old as the identification of HIV as the cause of the Acquired Immunodeficiency Syndrome (AIDS) in 1983 [1]. The elicitation of neutralizing antibodies (nAbs) by a vaccine is since believed to be imperative in either mediating sterilizing immunity or at least in preventing the establishment of latent reservoirs. Initial optimism was raised in the early 1990s when it was reported that vaccination with antigen preparations including whole inactivated virus, purified recombinant envelope (Env) proteins, and envelope-derived V3-specific peptides led to protection or a significant delay of infection of chimpanzees from a close to homologous i.v. challenge with a lab-adapted virus strain (HIV-1 IIIB) [2]. The clinical outcome was at that time attributed to sustained and high titers of virus neutralizing antibodies. These initial signs of hope, however, quickly gave way to fundamental sobering upon findings from numerous preclinical and clinical studies, including two phase III efficacy trials (VAX003 and VAX004), which proved that the neutralizing antibody responses induced by Env containing vaccine preparations such as the recombinant gp120s (AIDSVAX B/B and AIDSVAX B/E) used in the two phase III trials were largely strain-specific, lacked breadth and failed to neutralize primary isolates [3].

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