RSV F protein: An attractive target for therapeutic intervention

Sep 12, 2019
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Respiratory syncytial virus (RSV) causes severe acute lower respiratory tract infection leading to bronchiolitis and/or pneumonia in infants and the elderly, resulting in considerable mortality and morbidity. Unfortunately, an effective prophylactic modality, across most at-risk populations, is not yet available.  Antimicrobial stewardship is the call of current times aiming primarily to reduce spread of infections caused by multidrug-resistant organisms and improve patient outcomes.  Due to often similar clinical presentations with bacterial infections, many viral infections, such as those caused by RSV, are treated with anti-bacterial agents, negatively impacting public health beyond the primary infection.   For several bacterial and viral diseases, use of antibodies to prevent or treat the infections has been proposed and practiced (palivizumab for RSV; bezlotoxumab for recurrence of C. difficile infection). Infectious diseases are unique from other diseases, as real-life experiences in dealing with these pathogens may be employed to guide us to develop a road map for designing therapeutic interventions and prophylaxis. This process has been aided by advances in the isolation of human monoclonal antibodies (mAbs). Several mAbs are in clinical development for RSV as a passive immunization in infants, where active vaccination approaches are challenged to provide near-immediate protection due to the immaturity of the immune-system in this population.

The fusion (F) protein of RSV is considered to be a major antigenic target for the neutralizing antibodies, as it is more immunogenic and highly conserved than the RSV G protein, the other major surface antigen. Therefore, the majority of the vaccine and antibody approaches which are currently being explored are focused on the F protein.  Palivizumab (targeting antigenic site II on the F-protein) is the only approved mAb for the prevention of RSV infection in high-risk pre-term infants. Palivizumab resistant RSV mutants have been reported but are infrequent. In contrast, suptavumab or REGN222 (targeting site V on the F-protein), failed to meet its primary end-point in clinical trials due to circulation of an RSV B strain carrying mutation in the antibody binding site rendering the virus resistant to neutralization. These results underscore the importance of the epitope choice when targeting the RSV F protein with the monoclonal antibodies.

In the current manuscript we report on the isolation of an antibody (RB1) from human memory B-cells that maps to site IV on the RSV F protein. A survey of >3000 complete F sequences from RSV A and B strains reported in the GenBank indicates that the binding site for RB1 is 99.9% conserved. In preclinical studies, RB1 is equipotent across RSV clinical isolates belonging to diverse members of the F phylogenetic tree. Consistent with these findings, it has proven challenging to raise RB1 resistant RSV mutants in the laboratory.  Most of the RB1 resistant mutants which have been isolated to date display lower fitness in vitro, highlighting the importance of site IV to the function of F in RSV replication. RB1 is currently being evaluated in early stage clinical studies to prevent RSV infection in infants.

Kalpit A Vora

Distinguished Scientist, Merck and Co. Inc;

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