From setbacks to success: lessons from the journey of RSV vaccine development

Abstract

Respiratory syncytial virus (RSV) causes high worldwide infant mortality, as well as a high disease burden in the elderly. Efforts in vaccine development over the past 60 years have recently delivered three approved vaccines and two monoclonal antibodies (mAbs). Looking back at the eventful history of RSV vaccine development, several factors can be identified that have hampered the developmental pathway, including the occurrence of enhanced RSV disease (ERD) in the first vaccine attempt and the difficulty in characterizing and stabilizing the pre-fusion F protein as a vaccine target. Moreover, the need for large trials to test vaccine efficacy, usually done late in development, and the lack of a correlate of protection (CoP) result in significant uncertainties in RSV vaccine development. The use of controlled human infection models (CHIMs) may provide a solution for some of these problems: through swift, cost-efficient and closely monitored assessment of vaccine safety and efficacy in early clinical phases, vaccines can either 'fail fast' or show results supporting further investments. Moreover, CHIMs facilitate the assessment of disease and could assist in the identification of a CoP supporting late-stage development. Although some factors may affect translatability to real-world vaccine efficacy, CHIMs can support the clinical development pathway in various ways. We advocate for, and demonstrate, a conceptual and rational design of RSV vaccine development. Assessing protective efficacy early on would result in the most cost-efficient pathway and identification of target populations should be done as early as possible. For RSV, elderly individuals and people in low- and middle-income countries are high-impact populations for RSV prevention. While RSV immunization is now available in certain regions, global access is not accomplished yet, and worldwide prevention does not seem within reach. Quick and cost-effective assessments of candidates currently in the pipeline could contribute to future successes in the battle against RSV.

Keywords: RSV; clinical development; controlled human infection model; therapeutic; vaccine.

Figure 1.

The F protein undergoes conformational changes after fusion with the human cell. Source: Illustration by F. van Meurs.

Figure 2.

(a) A conceptual illustration of the time saved to a go/no-go decision for further development of a compound, by using a CHIM instead of following the conventional pathway of clinical development. (b) Comparison of the time and costs spent in clinical testing of the RSV F nanoparticle vaccine with GS-5806, both having failed to meet clinical endpoints. The use of a CHIM has facilitated GS-5806 to ‘fail fast’, saving up to 4 years and over €83M in estimated costs.

Figure 3.

Four essential questions in RSV vaccine development, entered in the question optimizing tool. For every question, estimated costs and PoS are entered. In this example, we’ve used a total out-of-pocket project cost of €80M and an estimated revenue of €800M, based on the numbers used by Roestenberg et al. PoS, probabilities of success; RSV, Respiratory syncytial virus.

Figure 4.

A conceptual, question-based approach visualized by a pathway of key questions in vaccine development. Here, an equal distribution of costs and probability of success is demonstrated, resulting in equal project values of the different routes (see lower left corner). PoS, probabilities of success; RSV, Respiratory syncytial virus.

Figure 5.

Applying the conceptual pathway to the RSV field results in a shift towards a more realistic distribution of PoS. The most cost-effective route involves early assessment of protective efficacy and the target population (Optimal route and Second best route). The User-defined route, starting with investigation of immunogenicity and therapeutic window, results in a significantly lower project value. PoS, probabilities of success; RSV, Respiratory syncytial virus.

Figure 6.

Using a CHIM may result in higher costs (e.g. €2M), but also increases the PoS of assessment of protective efficacy (e.g. by 4%). Early assessment of protective efficacy and target population remains more cost-effective when compared to the User-defined route, in which protective efficacy is investigated in a later stage. The overall project value in this figure is higher than in Figure 5, demonstrating the added value of using a CHIM despite an increase in financial investments.