Sequential Immunization Elicits Broadly Neutralizing Anti-HIV-1 Antibodies in Ig Knockin Mice

Abstract

Summary A vaccine that elicits broadly neutralizing antibodies (bNAbs) against HIV-1 is likely to be protective, but this has not been achieved. To explore immunization regimens that might elicit bNAbs, we produced and immunized mice expressing the predicted germline of PGT121, a bNAb specific for the V3-loop and surrounding glycans on the HIV-1 spike. Priming with an epitope modifiied immunogen designed to activate germline antibody-expressing B cells, followed by ELISA-guided boosting with a sequence of directional immunogens, native-like trimers with decreasing epitope modification, elicited heterologous tier-2 neutralizing responses. In contrast, repeated immunization with the priming immunogen did not. Antibody cloning confirmed elicitation of high levels of somatic mutation and tier-2 neutralizing antibodies resembling the authentic human bNAb. Our data establishes that sequential immunization with specifically designed immunogens can induce high levels of somatic mutation and shepherd antibody maturation to produce bNAbs from their inferred germline precursors.

Optimal immunization cocktails can promote induction of broadly neutralizing Abs against highly mutable pathogens

“…Alternatively, the most efficient strategy may be sequential immunization followed by a mixture of variant Ags, as in ref. 35. Study of these situations to determine optimal conditions as we report here, both computationally and experimentally, is an important direction of future research.…”

“…These in silico predictions were tested in model experiments in mice. A recent report (35) provides further experimental support for this strategy. Luo and Perelson (36) subsequently reported that, during the coevolution of viral strains and Ab responses after infection, Ab breadth increased with the number of variant Ags and the mutational distances separating them.…”

“…Enormous advances are being made in isolating bnAbs against HIV from patients (10-15), understanding the evolutionary pathways that lead to bnAbs in individuals (23)(24)(25)(26)(27)(28), and developing immunogens to activate the germline B cells that can mature into bnAbs (17)(18)(19)(20)(21)35 (3,6,8,20,22,34). Our past work leading to this conclusion considered variant Ags separated by relatively large mutational distances.…”

Improving the Expression and Purification of Soluble, Recombinant Native-Like HIV-1 Envelope Glycoprotein Trimers by Targeted Sequence Changes

“…This type of narrow-specificity response may serve as a necessary starting point for strategies intended to create neutralization breadth (7,(33)(34)(35)(36)(37)(38)(39).…”

EDiP: the Epitope Dilution Phenomenon. Lessons learnt from a malaria vaccine antigen and its applicability to polymorphic antigens

“…Given previous observations for malaria AMA1 and influenza HA, it would be interesting to test an HIV vaccine comprised of several Env proteins from different clades, preferably the native (SOSIP conformation [75]) expressed on a polyvalent VLP. Indeed, mixtures of five native-like SOSIPs differing in the variable loops have recently been used as a final boost for the induction of PGT121 like bnAb [76]. However, the full potential of this strategy, especially the expression of multiple variants on a single particle, has not yet been explored.…”