Recent advances in HIV-1 envelope-based vaccine designs for guiding broadly neutralizing antibody response.

Despite decades of intensive research, a protective prophylactic HIV-1 vaccine remains elusive. Considerable efforts have been made in developing HIV-1 vaccines which are capable of neutralizing diverse clades by utilizing conserved epitopes on the HIV-1 envelope glycoprotein (Env). However, traditional Env immunogens typically elicit only clade-specific neutralizing antibodies (nAbs), underscoring the need for novel strategies to trigger rare B cell precursors and then steer affinity maturation toward broadly neutralizing antibody (bnAb) induction. In recent years, diverse innovative vaccine antigen design strategies have been explored to induce protective bnAb response. In this review, we discuss the key technological advances in Env-based vaccine design, emerging immunization strategies, and insights from the recent clinical trials. It further provides a unique perspective on pediatric/infant-derived immunogen strategies. Ongoing collaborative efforts in rational immunogen design, optimized delivery strategies, and strategic immunization regimens will be critical for developing a vaccine capable of eliciting durable protective bnAb responses against HIV-1.