Respiratory syncytial virus prevention within reach: the vaccine and monoclonal antibody landscape

Abstract

Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a respiratory syncytial virus vaccine or immunoprophylaxis remain highly active. 33 respiratory syncytial virus prevention candidates are in clinical development using six different approaches: recombinant vector, subunit, particle-based, live attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. Nine candidates are in phase 3 clinical trials. Understanding the epitopes targeted by highly neutralising antibodies has resulted in a shift from empirical to rational and structure-based vaccine and monoclonal antibody design. An extended half-life monoclonal antibody for all infants is likely to be within 1 year of regulatory approval (from August, 2022) for high-income countries. Live-attenuated vaccines are in development for older infants (aged >6 months). Subunit vaccines are in late-stage trials for pregnant women to protect infants, whereas vector, subunit, and nucleic acid approaches are being developed for older adults. Urgent next steps include ensuring access and affordability of a respiratory syncytial virus vaccine globally. This review gives an overview of respiratory syncytial virus vaccines and monoclonal antibodies in clinical development highlighting different target populations, antigens, and trial results.

Figure 1:. Pediatric RSV Disease Burden: Key facts and figures

A. Contribution to RSV for worldwide pneumonia: Approximately one-third of worldwide pneumonia is caused by RSV. B. RSV-related deaths: More than 99% of the RSV pediatric global mortality burden occurs in LMICs. Access to care seems a key driver of the inequitable distribution of the mortality burden as less than one fourth of these children have access to an intensive care. At least half of this burden was previously hidden, as it occurs out-of-hospital. Recently the out-of-hospital burden has been characterized and is distinct from the in-hospital mortality burden which has implications for global vaccine development: out-of-hospital children die at a younger age and risk factors are linked to poverty instead of underlying conditions. C. Total Costs: Estimated direct associated with RSV exceed 3 billion USD in LMICs, with additional direct non-medical and indirect costs. D. Expected vaccine impact: The cost-effectiveness and potential impact of maternal immunization (MI) vs mAb (monoclonal antibody) has been estimated in deaths averted and discounted DALYs (disability adjusted life-years).

Figure 2:. Overview of vaccine candidates by preventive approach

Pre- and post-fusion proteins were created with RCSB PDB 5C6B^, and 3RRT^,, respectively.

Figure 3:. RSV vaccine and mAb candidates by target population.

Vaccine candidates and mAbs are categorized into three different target populations: (1) pediatric, (2) maternal, and (3) older adults and clinical phase of development: Phase I, II, or III. Different immunization approaches are indicated by the legend at the bottom. The route of administration is indicated in the small purple circles at the right: (1) intramuscular (IM), (2) intranasal (IN), (3) intradermal.

Figure 4.. Historical perspective of RSV vaccine and immunoprophylaxis development over the last ten years and expected market access

Candidates that are in ongoing development (purple) or no longer in development (red) are presented at the timing of the clinical trials rounded off to full years. The darkness of the color represents the furthest development (Phase I – III) of the candidate. Candidates with multiple clinical trials are connected with full or dotted lines to show the speed of development. Live attenuated viruses by the same manufacturer are summarized in one box as development of these candidates largely overlaps. The timing of current and previous reviews are shown at the top.