Respiratory Syncytial Virus – the Quest for Effective Prevention

Respiratory syncytial virus (RSV) is an RNA virus that causes lung and respiratory tract infections. It is a leading cause of morbidity and mortality, and is the second largest cause of death in children under 1 year of age. In 2017, it was estimated that RSV causes around 33.1 million episodes, 3.2 million hospital admissions, and 59,600 in-hospital deaths annually among children younger than 5 years.¹ Children infected with RSV also have a higher risk of subsequently developing chronic conditions, including allergic rhino-conjunctivitis, recurrent wheezing and asthma.² In addition, the virus is a significant problem in certain adult populations, including the elderly, people with cardiopulmonary diseases and immunocompromised hosts.³

Despite many attempts to identify effective pharmacologic strategies, treatment is limited to supportive care, which includes respiratory support combined with appropriate fluid and nutrition management.⁴ Preventative strategies, therefore, have the potential to improve global health among vulnerable children. The current standard of care for prevention of RSV infections is passive prophylaxis with palivizumab (Synagis, Swedish Orphan Biovitrum AB, Stockholm, Sweden), which can reduce recurrent wheeze in children with RSV.⁵ However, palivizumab is only approved for use in premature infants and other children at the highest risk.⁶

Papivizumab is a monoclonal antibody that attacks the RSV surface fusion glycoprotein (F protein), a genetically stable antigen. In February 2019, another prophylactic monoclonal antibody, MEDI8897 (AstraZeneca), received an FDA Breakthrough Therapy designation and has entered a phase III study following the findings of a phase IIb trial, which met its primary endpoint of a statistically-significant reduction in the incidence of medically-attended lower respiratory tract infection (LRTI) caused by RSV, for 150 days after dosing in healthy preterm infants. MEDI8897 may also offer the advantage of only requiring one dose during a typical 5-month RSV season, unlike papivizumab, which requires monthly injections.⁷ Another monoclonal antibody with extended half-life, MK-1654 (Merck, Sharp & Dohme, Kennilworth, NJ, USA), which targets the RSV F protein site IV, is currently being evaluated in a phase II clinical trial (NCT03524118) for the prevention of RSV infection in infants.

The RSV F protein has also provided a target for new vaccine development. However, the F protein is a shape-shifter, flipping from a neutralisation-sensitive pre-fusion conformation to a post-fusion, less sensitive form. Producing RSV vaccines using traditional methods usually leads to post-fusion F proteins and a poor antibody response. Various novel approaches to vaccine production are therefore being investigated, including particle-based vaccines, in which the RSV F protein is presented in a nanoparticle format, enhancing its immunogenicity; subunit vaccines using the F protein in the pre-fusion conformation; live attenuated viruses; and recombinant vectored viruses.

In recent years, several vaccine trials have ended in failure, due to suboptimal neonatal immune response. The development of an RSV vaccine has been hindered by a number of problems: there is no optimal animal model; repeated infections may occur throughout life, and we do not have effective serological markers of protection to RSV. This has led to the development of fail-fast systems, which are designed to report failure and halt product development, rather than continue developing a product that unlikely to succeed in late-stage clinical trials.⁸

Despite this, high-profile clinical trials are still failing to meet objectives. One strategy that has received considerable recent attention is maternal immunisation, allowing the transfer of maternal IgG antibodies across the placenta to foetal circulation during the third trimester of pregnancy. ResVax (Novavax, Rockville, MD, USA), is an aluminium-adjuvanted RSV fusion protein recombinant nanoparticle vaccine that has been designed to prevent RSV in newborns through maternal immunisations. However, the recent phase III Prepare™ trial, involving 4,636 pregnant women, did not meet its primary objective of prevention of medically significant RSV lower tract respiratory infection (LRTI).⁹ These disappointing data may not signal the end of the line for ResVax. The FDA has recommended that Novavax conduct an additional phase III study to investigate efficacy against medically significant RSV disease in infants born to mothers vaccinated with ResVax.¹⁰

Despite the setback of the Prepare study, optimism remains high, with several other vaccine products showing promising clinical outcomes. Other maternal immunisation RSV candidates are currently being evaluated, including a Pfizer candidate with a stable prefusion F protein that is currently in phase II development (NCT04032093) following promising findings in a phase I study in healthy adults.¹¹

Several vectored RSV vaccines are currently being evaluated in clinical trials. One of the most advanced is Ad26.RSV.preF (Janssen, Beerse, Belgium), a replication-incompetent adenoviral vector vaccine using the pre-fusion form of the RSV F protein as an antigen. A recent study in healthy adult models showed that a single immunisation with Ad26.RSV.preF significantly reduced nasal viral load compared to placebo, as well as significantly reducing the number of RSV infections. This vaccine is the first adult RSV vaccine candidate to show protection against upper respiratory disease.¹² Another candidate, MVA-BN RSV (Bavarian Nordic, Hellerup, Denmark) encodes RSV surface proteins F and G as well as internal proteins N and M2 in a viral vector backbone, and has shown positive findings in a phase I study in elderly (≥60 years old) patients,¹³ with a phase III study planned.

In conclusion, despite a number of setbacks, vaccine development for RSV is progressing rapidly, with several promising candidates in late stage clinical trial development. It seems likely that a safe and effective RSV vaccine will be launched in the coming years.

 

References

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