Progress toward active or passive HIV-1 vaccination

Abstract

AIDS is a preventable disease. Nevertheless, according to UNAIDS, 2.1 million individuals were infected with HIV-1 in 2015 worldwide. An effective vaccine is highly desirable. Most vaccines in clinical use today prevent infection because they elicit antibodies that block pathogen entry. Consistent with this general rule, studies in experimental animals have shown that broadly neutralizing antibodies to HIV-1 can prevent infection, suggesting that a vaccine that elicits such antibodies would be protective. However, despite significant efforts over the last 30 years, attempts to elicit broadly HIV-1 neutralizing antibodies by vaccination failed until recent experiments in genetically engineered mice were finally successful. Here, we review the key breakthroughs and remaining obstacles to the development of active and passive HIV-1 vaccines.

Figure 1.

Requirement for sequential immunization. (A) Panel illustrates the finding that HIV-1 antibodies are highly somatically mutated. (B) Panel shows that germline-reverted antibodies fail to bind to most HIV-1 antigens. (C) Panel illustrates the observation that HIV-1 and bNAbs develop in sequence over time. (D) Panel shows the results of knock-in mouse immunization experiments that showed that multiple immunogens would be required for bNAb development.

Figure 2.

Linking sequential immunization to somatic mutation and bNAb development. The figure illustrates the immunization scheme that led to bNAb development in mice that carry the PGT121 germline gene. The initial immunogen had the highest affinity for the germline-reverted antibody, and subsequent immunogens had decreasing affinities. Somatic mutation increased with immunization.