Designing an HIV-1 envelope glycoprotein (Env) that can induce broadly neutralizing antibodies in humans remains one of the great challenges in biomedical research. Monomeric gp120 has repeatedly failed to induce cross-neutralizing antibodies in clinical trials. Spearman et al. vaccinated uninfected volunteers with a trimeric gp140 protein. They found that the vaccine was safe and induced neutralizing antibody responses against the homologous virus, but not cross-neutralizing responses. The results reinforce the notion that our Env vaccine design needs to improve.