All Eyes on the Prefusion-Stabilized F Construct, but Are We Missing the Potential of Alternative Targets for Respiratory Syncytial Virus Vaccine Design?

Abstract

Respiratory Syncytial Virus (RSV) poses a significant global health concern as a major cause of lower respiratory tract infections (LRTIs). Over the last few years, substantial efforts have been directed towards developing vaccines and therapeutics to combat RSV, leading to a diverse landscape of vaccine candidates. Notably, two vaccines targeting the elderly and the first maternal vaccine have recently been approved. The majority of the vaccines and vaccine candidates rely solely on a prefusion-stabilized conformation known for its highly neutralizing epitopes. Although, so far, this antigen design appears to be successful for the elderly, our current understanding remains incomplete, requiring further improvement and refinement in this field. Pediatric vaccines still have a long journey ahead, and we must ensure that vaccines currently entering the market do not lose efficacy due to the emergence of mutations in RSV's circulating strains. This review will provide an overview of the current status of vaccine designs and what to focus on in the future. Further research into antigen design is essential, including the exploration of the potential of alternative RSV proteins to address these challenges and pave the way for the development of novel and effective vaccines, especially in the pediatric population.

Keywords: RSV; vaccine.

Figure 1

Schematic overview of an RSV virion (A) and its genome (B). NS1 = non-structural protein 1, NS2 = non-structural protein 2, P = phosphoprotein, M = matrix protein, SH = small hydrophobic protein, G = attachment glycoprotein, F = fusion protein, M2-1 = transcription processivity factor, M2-2 = transcriptional regulatory protein and L = large polymerase protein. F and G are both presented as hypothetical trimers. While F is likely a trimer on the virion, the oligomeric nature of G is still not known. Created with BioRender.com.

Figure 2

Schematic overview of the maturation process of the F protein. In the top panel, the inactive RSV F0 precursor protein with the different domains, including the two subunits F1 and F2 with the corresponding cleavage sites (I and II), p27, SP = signal peptide, FP = fusion peptide, HRA = heptad repeat A, HRB = heptad repeat B, TM = transmembrane peptide, CT = cytoplasmic. Below, the active F protein is depicted. p27 is removed, and two disulfide bridges are formed between F1 and F2. Six N-glycosylation sites are located at the respective amino acid positions (N27, N70, N116, N120, N126 and N500) [47]. Image created with BioRender.com (2023).

Figure 3

Trimeric prefusion and postfusion conformations of the F protein are shown, in which the different antigenic sites are color-coded. Antigenic sites II and IV are present on both the pre- and postfusion conformations, while sites Ø and V are prefusion-specific. On the right, the relative neutralizing potency of each site is displayed. It should be noted that these differences in potency could also partially reflect differences in antibody affinity or specific properties of the mAbs. Created with PyMOL and BioRender.com.

Figure 4

Overview of current vaccines and immunoprophylaxis in development and on the market. Classification according to the antigen construct used in the vaccine. Created with BioRender.com.