Efforts to broaden HIV‐1‐specific immunity by boosting with heterologous peptides or envelope protein and the influence of prior exposure to virus

Abstract: In two previous studies, we have demonstrated the successful protection of human immunodeficiency virus type 1 (HIV‐1)‐vaccinated rhesus macaques from challenge with SHIVSF13 with envelop immunogens derived from the closely related HIV‐1SF2 strain. Here we report on two follow‐up studies in which we aimed to broaden immunity in order to elicit protection from a more diverse heterologous challenge with SHIVSF33. In the first study, animals were boosted once with HIV‐1SF33 V2 and V3 peptides that were cross‐linked to influenza immunestimulating complexes (ISCOMs). In the second study, monkeys were boosted twice at 12‐week intervals, using a heterologous recombinant gp120 derived from HIV‐1SF33 that was either incorporated into ISCOMs or mixed with the MF59 adjuvant. In both studies, the animals were challenged with 50 monkey infectious doses of SHIVSF33 4 weeks after the final boost. All controls became readily infected with the heterologous challenge virus SHIVSF33. Neither boosting with heterologous SF33 peptides or gp120 afforded protection from infection to SF2‐vaccinated animals that had previously resisted SHIVSF13 challenge. These results demonstrate the importance of developing vaccine strategies that are capable of generating broad immune responses early in the immunization protocol. Furthermore, these findings may illustrate the potential pitfalls of early antigenic sin.