Respiratory Syncytial Virus Infection: Old Challenges and New Approaches

Respiratory syncytial virus (RSV) is an orthopneumovirus that belongs to the Pneumoviridiae family. There are 2 antigenic subgroups, A and B, which can cocirculate during the same season. The nonsegmented, single-stranded, negative sense genome contains 10 genes that encode 11 proteins. Three are nonstructural proteins (NS1, NS2, and M2-2), and 8 are structural proteins. Three of the structural proteins are in the surface viral membrane: the small hydrophobic (SH), the attachment (G), and the fusion (F) glycoproteins; and 5 are internal proteins (N, P, M, M2-1, L). SH is not required for initiating infection, but F and G are crucial for the infectivity and pathogenesis of the virus. The G protein targets the ciliated cells of the airways and mediates adherence to the host cells. The F protein initiates viral penetration by fusing viral and cellular membranes, and late in the infection it causes infected cells to fuse inducing the characteristic syncytia.

Respiratory syncytial virus (RSV) remains one of the great threats to child health associated with considerable acute and long-term morbidity [1–3]. Worldwide, in infants and toddlers, RSV is the leading cause of viral lower respiratory tract infection ([LRTI] including bronchiolitis and pneumonia). In adults >65 years, RSV is responsible for 5%–10% of LRTI, with hospitalization rates of 255 per 100 000 and >14 000 deaths each in year in United States, especially in those with chronic medical conditions [4, 5]. Globally, it is estimated that RSV causes 33 new million episodes of acute LRTI in children <5 years of age, resulting in 3.6 million hospitalizations and ∼100 000 RSV-attributable deaths annually. Up to 97% of RSV-attributable deaths occur in low- and middle-income countries, and it represents the second most common cause of infant mortality [6, 7]. In addition, RSV is a major pathogen for immunocompromised individuals, and it has been associated with the development of persistent wheezing and asthma [8]. It is ubiquitous with worldwide distribution and causes yearly predictable outbreaks until 2020 when RSV skipped a whole season during the first year of the coronavirus disease 2019 (COVID-19) pandemic [9]. Subsequently, the relaxation of the nonpharmaceutical interventions implemented during the COVID-19 pandemic resulted in off-seasonal surges of RSV infection in 2021 and 2022. The lack of RSV circulation and exposure for more than 1 year has resulted in a reduction of RSV-neutralizing antibodies in childbearing and breastfeeding women and thus a bigger pool of RSV-susceptible children (immunity debt) [10, 11]. This combined with possible different RSV lineages that were circulating prepandemic could explain the substantially increased volume of children currently infected with RSV that occurred in the Unites States, Canada, and other parts of the world [12]. It is interesting to note that there has not been a parallel increase in the number and severity of RSV cases in older adults, who may be adhering to stricter public health measures [13].

Development of RSV vaccines has been remarkably challenging. Respiratory syncytial virus affects infants with an immature immune system, and it has specific genes (NS1 and NS2) with unique ability to hamper interferon and antibody responses. In addition, the initial formalin-inactivated vaccine evaluated in the 1960s was associated with severe adverse events; this setback considerably slowed major investments and further developments. A breakthrough for RSV prevention was the development in the 1990s of an anti-RSV monoclonal antibody ([mAb] palivizumab), which established the proof-of-concept that high-titer neutralizing antibodies can significantly reduce severe RSV disease [14]. This approach was very effective in high-risk children; unfortunately, the need for monthly injections and the cost limited its application as a universal strategy to prevent RSV in all infants.

Two circumstances significantly reinvigorated the efforts to develop RSV vaccines and mAbs. First, the epidemiologic studies demonstrating its impact on global morbidity and mortality already mentioned, and second the resolution of the structure of the RSV fusion (F) protein in its 2 conformations: the metastable prefusion (preF) and the postfusion (postF) forms [15]. This seminal observation facilitated the detailed mapping of the different antigenic sites in RSV F, and the discovery that certain antigenic sites only present in the preF form represent the most potent neutralizing epitopes. These scientific discoveries set the basis for structure-based vaccine design and encouraged global health organizations, biotech, and vaccine companies to focus on developing novel vaccines and mAbs targeting mostly RSV preF, but also other antigens. The progress and ongoing efforts have been remarkable, and we are experiencing a true renaissance in the field of RSV prevention [16].

Prevention of RSV infections will require different strategies for the different age and risk groups. Several companies using different vaccine platforms recently reported studies demonstrating significant reductions in severe RSV LRTI among individuals ≥60–65 years. An adenovirus 26 expressing preF/combined with preF protein vaccine (Ad26.RSVpreF/RSVpreF; Janssen) (Figure 1A) demonstrated 80% efficacy for prevention of severe RSV lower respiratory tract disease (LRTD) [17]. An adjuvanted PreF3 (RSVPreF3 OA; Glaxo) vaccine (Figure 1B) was shown to be associated with 82.6% reduction of RSV LRTD [18]. A bivalent RSV preF vaccine (Pfizer) (Figure 1C) had an efficacy of 85.7% reducing RSV LRTI with >3 symptoms in this population [19]. These early results are encouraging, but obviously it will be fundamental to review the complete datasets and peer-reviewed manuscripts. Nevertheless, it is important to put these findings in a historical context, because it is the first time in decades that not only 1 but several RSV vaccines appear to demonstrate major efficacy in reducing severe RSV infections in older individuals.

With respect to young children, the traditional approach of actively immunizing infants in early life starting at approximately 2 months of age has been abandoned for several reasons. First, very young infants, less than 2–4 months of age, are frequently affected and represent the greatest proportion of RSV-associated hospitalizations, and second because of the inability of their immune system to mount an effective antibody response against RSV. These observations have inspired alternative approaches, and 2 different strategies are being pursued to be able to provide young infants with protective antibodies against RSV. Maternal immunization is an attractive, established strategy, with proven efficacy for prevention of tetanus, pertussis, and influenza in young infants. An initial trial evaluating a prefusogenic RSV F particle (Novavax) demonstrated safety and reductions in RSV LRTI, but unfortunately it did not meet the primary endpoint [20]. Studies using a bivalent RSV preF vaccine (Pfizer) (Figure 1C) in pregnant women reported excellent immunogenicity and antibody transfer across the placenta [21]. A recent press release of the phase 3 trial reported a reduction of 81.8% of severe RSV LRTI in infants during the first 90 days of life and of 69.4% over the 6 months follow-up period [22]. Again, this study represents the first suggestion that a maternal vaccine may significantly reduce severe RSV infections in infants.

An alternative strategy for RSV prevention in infants is the direct administration of mAbs with markedly improved characteristics compared with the first-generation mAb, palivizumab. The newly designed mAbs have increased potency, because they are directed to preF highly neutralizing epitopes, and also a prolonged half-life related to the introduction of the YTE mutation in the Fc region. This extended half-life provides adequate serum concentrations for at least 150 days, which makes it possible for a single mAb dose to provide protection for the complete RSV season. In studies conducted in late preterm (>35 weeks' gestational age) and term infants, a single dose of nirsevimab (AstraZeneca/Sanofi), a mAb directed to site O in RSV preF (Figure 1D), was associated with a 76.4% reduction of RSV medically attended LRTI and of 76.8% of RSV hospitalization during the 150-day follow-up period [23, 24]. A second mAb, clesrovimab (Merck), directed to site IV, which is present in the preF and postF conformations of the RSV F protein (Figure 1E), has also demonstrated excellent serum concentrations and preliminary efficacy in phase 1b/2a studies [25].

These are exciting achievements. The next step is to further review the complete data and efficacy of these strategies and to begin planning their implementation in real-life clinical settings in both resource-rich and resource-limited countries. Important questions remain, such as understanding the optimal time during pregnancy for maternal vaccination and as well when to administer mAbs to infants in relation to RSV seasonality in the different parts of world. Additional issues include the need to better define the importance of providing cross-protection for both RSV A and B strains and to monitor the potential emergence of RSV variants that could escape these preventive interventions. In addition, it will be critical to monitor the impact of preventing severe RSV infection during the initial season and whether that may affect the expected normal development of RSV immunity and memory. More importantly, despite these major advances, we still need vaccines for older infants and children that cannot benefit from these passive immunization strategies but still account for significant morbidity. Despite these challenges, this a remarkable time, full of opportunities to begin to significantly reduce the morbidity and mortality associated with RSV in all infants, not only during the acute disease but possibly also the long-term chronic respiratory morbidity. It is up to us to design the optimal studies and implementation strategies to make this happen.

Figure 1.

Respiratory syncytial virus (RSV) vaccine platforms and monoclonal antibodies. The prefusion (preF) RSV form of the protein F has been successfully included in different vaccine constructs, including an adenovirus 26 (Ad26) vaccine expressing preF combined with preF protein vaccine (Janssen) (1A), an adjuvanted RSV preF3 (Glaxo) (1B), and a bivalent RSV A and B preF vaccine (Pfizer) (1C). In addition, newer generation monoclonal antibodies with extended half-life due to modifications in the Fc region (YTE technology) are also undergoing clinical trials targeting either site O present only in the prefusion form of the F protein (nirsevimab [1D]) or site IV, which is present in both the preF and postfusion (postF) conformations (clesrovimab [1E]).

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Notes

Financial support. OR and AM are supported in part by National Institutes of Health (NIH) Grants AI131386 and AI168632. RR-F is supported in part by grants from the FIS (Fondo de Investigacion Sanitaria: PI 16/00822 and PI 21/00840 funded by Instituto de Salud Carlos III (ISCIII), Spain.

Reference

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