This study investigates the role of cross-reactive anti-prM antibodies in the human immune response to dengue virus infection. The authors generated a panel of human monoclonal antibodies from dengue-infected individuals and found that anti-prM antibodies dominated the response, showing high cross-reactivity among the four serotypes of dengue virus. These antibodies, despite their cross-reactivity, did not neutralize infection but potently promoted antibody-dependent enhancement (ADE) of viral replication in Fc-receptor-bearing cells. The partial cleavage of prM from the viral surface reduces the density of antigen available for neutralization, making dengue viruses susceptible to ADE by anti-prM antibodies. This finding has implications for vaccine design, suggesting that vaccines should minimize the anti-prM response to reduce the risk of ADE. The study also highlights the importance of understanding the dynamics of prM cleavage and its impact on virus infectivity and immune evasion.This study investigates the role of cross-reactive anti-prM antibodies in the human immune response to dengue virus infection. The authors generated a panel of human monoclonal antibodies from dengue-infected individuals and found that anti-prM antibodies dominated the response, showing high cross-reactivity among the four serotypes of dengue virus. These antibodies, despite their cross-reactivity, did not neutralize infection but potently promoted antibody-dependent enhancement (ADE) of viral replication in Fc-receptor-bearing cells. The partial cleavage of prM from the viral surface reduces the density of antigen available for neutralization, making dengue viruses susceptible to ADE by anti-prM antibodies. This finding has implications for vaccine design, suggesting that vaccines should minimize the anti-prM response to reduce the risk of ADE. The study also highlights the importance of understanding the dynamics of prM cleavage and its impact on virus infectivity and immune evasion.