Codon-Pair Deoptimized (CPD) Intranasal RSV Vaccines: A Novel Strategy for Infant Protection

Respiratory syncytial virus (RSV) is considered the leading causative agent of acute lower respiratory infections in infants and young children worldwide, which makes it a major contributor to pediatric morbidity and mortality. Infants are especially susceptible to severe disease in early life, which underlines the urgent need for developing effective immunization strategies against this virus. However, the development of vaccines against RSV has long been associated with significant challenges. For example, initial attempts, especially those involving formalin-inactivated RSV, resulted in vaccine-enhanced respiratory disease upon subsequent infection, which set a significant safety obstacle for future vaccine candidates. Other challenges facing vaccine development against RSV include the short-lived immunity induced by natural infection, lack of clear correlates of immunity, and immune naivety in infants. Recent breakthroughs in structural virology and immunology have provided insights into protective immunity against RSV, especially regarding neutralizing antibodies that recognize the virus in its prefusion conformation of the viral F protein. Among promising vaccine candidates, intranasal live-attenuated vaccines have emerged as especially promising for infant immunization, especially considering their close mimicry of natural infection that can elicit systemic as well as mucosal immunity in the respiratory tract. A newly emerging approach for live-attenuated virus vaccine development is codon-pair deoptimization (CPD), which is based on synthetic recoding that reduces viral replicative capacity while maintaining intact protein sequences and structure. The preclinical results of CPD-based RSV candidates have provided evidence of such vaccines' ability to elicit robust immunity while maintaining favorable safety profiles. This review addresses the major challenges associated with the development of effective RSV vaccines for infant immunization, with particular emphasis on lessons learned from previous vaccine failures and recent advances in RSV vaccine development, particularly CPD-based attenuation strategies.