Structure-Based Design of Head-Only Fusion Glycoprotein Immunogens for Respiratory Syncytial Virus

Boyington, Jeffrey C.; Joyce, M. Gordon; Sastry, Mallika; Stewart-Jones, Guillaume B. E.; Chen, Man; Kong, Wing-Pui; Ngwuta, Joan O.; Thomas, Paul V.; Tsybovsky, Yaroslav; Yang, Yongping; Zhang, Baoshan; Chen, Lei; Druz, Aliaksandr; Georgiev, Ivelin S.; Ko, Kiyoon; Zhou, Tongqing; Mascola, John R.; Graham, Barney S.; Kwong, Peter D.

As immunogens i-693 and i-447 were both able to induce reasonable RSV-neutralizing antibodies, we further investigated their potential to focus the antibody response to head-only antigenic sites by heterologously boosting mice that had been primed twice with DS-Cav1. In each instance, the prime interval was three weeks and the boost interval was seven weeks. Such a boost may mimic the boosting of individuals who have been previously exposed to RSV. Notably, week 12 sera showed head-only boosting to elicit geometric mean titers for i-693 and i-447 of 14,844 and 12,998, respectively, which were statistically comparable with the mean titers for the RSV F DS-Cav1 control of 10,548 ( Fig 4B) . Interestingly, reversing the prime-boost (headonly prime followed by a DS-Cav1 boost) resulted in a significantly lower responses for both i-693 and i-447 (P = 0.0052 and 0.0354 respectively) (S5 Fig). Thus the dimeric i-693 and the trimeric i-447 did not appear to prime as well as the full length DS-Cav1, but they did appear to focus and to boost the head-directed neutralizing response.