The continuing need for therapeutic agents for respiratory syncytial virus infection

Respiratory syncytial virus (RSV) is a major cause of respiratory infections worldwide, with the most severe cases occurring in very young and in elderly individuals.^1–4 Infants and children having their first encounter with the virus are more likely to develop bronchiolitis and pneumonia, and even die. However, most deaths overall occur from infections of the elderly. In addition, immunocompromised individuals of any age are at greater risk of adverse outcomes.

An effective RSV vaccine has been sought for decades without success, although recent progress is encouraging, ⁵ including studies using molecularly altered RSV gene products^6–10 and studies of an attenuated virus resulting from rational design based on increased knowledge of RSV gene function. ¹¹ It must be noted that live attenuated vaccines will not be suitable for all populations at risk for RSV. ¹² Comprehensive tables detailing candidate vaccines in clinical phases of development, including for different target populations, have been published.^13–15 There is still a continuing need to contribute to current knowledge regarding innate and adaptive immunity to RSV, the mechanisms used by the virus to accomplish re-infection, and treatment approaches directed at RSV itself or designed to counteract the suppression of immune responses by RSV, as well as approaches to improved vaccine development that are likely to benefit the host upon subsequent natural challenge. Such investigations will support both the continued development of truly effective vaccines and will provide direction for the development of therapeutic agents.

RSV re-infection occurs throughout life, but subsequent infections are less severe.^16,17 Adult leukocyte donors have class I-restricted immunity against RSV that is characterized by the persistence, after clearance of infection, of circulating RSV antigen-specific human T cells. ¹⁷ However, the immune response does not prevent clinical re-infection even in the absence of RSV strain variation. Longitudinal studies of RSV infections in children showed that children can be naturally re-infected with the same strain of virus ¹⁸ and a single RSV isolate has been shown to cause repeated experimental symptomatic infections in adult volunteers. ¹⁶ The cellular and humoral defenses that are induced by an RSV challenge are likely to be offset at least partially by the ability of the naturally encountered infectious virus to counteract innate and especially adaptive immune responses. ¹⁹ This aspect makes it important to delineate as much as possible the immune response and correlates of protection, and it also suggests that RSV candidate vaccines that are being developed may not and perhaps should not be expected to prevent clinical natural re-infection. Such candidate vaccines should render a first infection in the young person less severe, akin to subsequent infections after a natural first encounter in childhood. ¹⁹ Such vaccines may also be expected to boost potentially waning immunity in the elderly, used at intervals to promote patient survival with the natural RSV infection.

Initial reports indicated the safety and immunogenicity of RSV prefusion F vaccines. ¹⁰ Recent reports of large phase 3 trials indicate the safety and potential efficacy of prefusion RSV F-based vaccines, specifically for older adults who are at increased risk of severe disease and death, ⁸ and for pregnant women and their infants. ⁹ The platforms included both adenovirus-based and adjuvanted prefusion protein-based vaccines. In May 2023, the U.S. Federal Drug Administration first approved an RSV vaccine, the GSK adjuvanted recombinant subunit prefusion F glycoprotein antigen for the elderly. In addition, mRNA-based vaccines are being developed and evaluated. Even if an RSV vaccine is licensed and widely used, it should be expected that many in the population will not respond adequately to the vaccine and/or will suffer severe enough re-infections that the availability of effective therapeutic anti-RSV agents will be required to fully address the challenges by RSV. Thus, effective therapeutic agents for RSV are likely to be needed, especially for high-risk populations, even after effective vaccine development. Limited immune function at the extremes of life (infancy and old age), and with immunosuppression due to disease or its therapy, combined with RSV effects on the recall immune response, make a continued search for effective anti-RSV antiviral agents an important partner to vaccine development.

Fortunately, an array of new therapies for RSV infection are being evaluated, targeting either viral entry or post-entry steps in viral replication. The agents include monoclonal antibodies, nucleoside analogs, anti-sense RNA, and fusion inhibitors, reviewed in detail elsewhere,^20–22 including comprehensive tables that detail those agents that are in clinical phases of development.^20,21 The agents are directed against the virus at different stages in its quest for replication in the host cell, whether a respiratory epithelial cell or perhaps a leukocyte responding to the challenge. Even agents for other indications, such as probenecid, are being evaluated for activity against RSV. ²³ It is not evident that there are agents under development that address the method(s) that RSV uses to attenuate and/or delay the hosts antiviral immune response. Data from a series of studies support the concept that recurrent RSV infection may be related at least in part to early RSV effects on lymphocyte function.^17,19,24 Studies have documented the existence of RSV-specific lymphocytes in peripheral blood from adults, ¹⁷ with robust proliferation in response to inactivated RSV but markedly reduced proliferation after exposure to infectious RSV. ²⁵ In fact, exposure to infectious RSV effectively inhibits the proliferative T-cell response to inactivated RSV. ²⁶

Studies addressing RSV-related subversion of immune responses may indicate important avenues for additional effective antiviral agent development. Thus, one can reasonably recommend the addition of such investigations to the ongoing effort to reduce or eliminate the morbidity and mortality associated with RSV infection.