Protection and mechanism of action of a novel human respiratory syncytial virus vaccine candidate based on the extracellular domain of small hydrophobic protein

Infections with human respiratory syncytial virus (HRSV) occur globally in all age groups and can have devastating consequences in young infants. We demonstrate that a vaccine based on the extracellular domain (SHe) of the small hydrophobic (SH) protein of HRSV, reduced viral replication in challenged laboratory mice and in cotton rats. We show that this suppression of viral replication can be transferred by serum and depends on a functional IgG receptor compartment with a major contribution of FcγRI and FcγRIII. Using a conditional cell depletion method, we provide evidence that alveolar macrophages are involved in the protection by SHe‐specific antibodies. HRSV‐infected cells abundantly express SH on the cell surface and are likely the prime target of the humoral immune response elicited by SHe‐based vaccination. Finally, natural infection of humans and experimental infection of mice or cotton rats does not induce a strong immune response against HRSV SHe. Using SHe as a vaccine antigen induces immune protection against HRSV by a mechanism that differs from the natural immune response and from other HRSV vaccination strategies explored to date. Hence, HRSV vaccine candidates that aim at inducing protective neutralizing antibodies or T‐cell responses could be complemented with a SHe‐based antigen to further improve immune protection. Synopsis Vaccination with the ectodomain of the small hydrophobic protein (SHe) controls pulmonary replication of human respiratory syncytial virus (HRSV). Combining SHe‐based antigens to vaccines that aim at inducing neutralizing antibodies could further improve immunoprotection against HRSV. SHe‐based vaccination induces SHe‐specific non‐neutralizing antibodies that reduce viral replication in two animal models. Pulmonary HRSV replication and associated morbidity are reduced by SHe‐specific immune serum. The reduction of viral replication by SHe‐specific antibodies strongly depends on Fcγ receptor I and/or III and at least partially on alveolar macrophages. HRSV‐infected cells, but not virions, are readily recognized by SHe‐specific antibodies. Graphical Abstract Vaccination with the ectodomain of the Small Hydrophobic Protein (SHe) controls pulmonary replication of Human Respiratory Syncytial Virus (HRSV). Combining SHe‐based antigens to vaccines that aim at inducing neutralizing antibodies could further improve immunoprotection against HRSV.