Cell-to-cell spread inhibiting antibodies constitute a correlate of protection against Herpes Simplex Virus Type 1 reactivations

Herpes simplex viruses (HSV) cause ubiquitous human infections. For vaccine development, knowledge concerning correlates of protection against HSV is essential. Therefore, we investigated if humans principally can produce highly protective cell-to-cell spread inhibiting antibodies upon natural infection and whether such antibody responses correlate with protection from HSV reactivation. We established a high-throughput HSV-1 GFP reporter virus-based assay and screened 2496 human plasma samples for HSV-1 cell-to-cell spread inhibiting antibodies. We conducted a survey among the blood donors to analyze the correlation between the presence of cell-to-cell spread inhibiting antibodies in plasma and the frequency of HSV reactivations. In total, 128 of 2496 blood donors (5.1 %) exhibited high levels of HSV-1 cell-to-cell spread inhibiting antibodies in the plasma. Such individuals showed a significantly lower frequency of HSV reactivations compared to subjects without sufficient levels of HSV-1 cell-to-cell spread inhibiting antibodies. This study provides two important findings: (I) a fraction of humans produce HSV cell-to-cell spread inhibiting antibodies upon natural infection and (II) such antibodies correlate with protection against recurrent HSV. Moreover, these elite neutralizers can provide promising material for hyperimmunoglobulin, the isolation of superior antiviral antibodies and information for the design of a vaccine against HSV. ImportanceHerpes simplex virus 1 infections can cause painful mucosal lesions at the oral or genital tract and severe, life threatening disease in immunosuppressed patients or neonates. There is no approved vaccine available, and the emergence of drug resistances especially in long time treated patients makes the treatment increasingly difficult. We tested 2496 people for HSV-1 cell-to-cell spread inhibiting antibodies. Five percent exhibited functional titers such antibodies and showed significantly lower risk of reactivations, uncovering cell-to-cell spread inhibiting antibodies as a correlate of protection against Herpes simplex virus reactivations. Isolation of the cell-to-cell spread inhibiting antibodies from B-cells of these donors may contribute to develop novel antibody-based interventions for prophylactic and therapeutic use and provide starting material for vaccine development.