The COVID-19 pandemic established that, when push comes to shove, successful vaccine development and deployment can be conducted at breakneck speed, even when largely untried and untested technologies are involved. A lower-profile industry success story has a very different timeline, as after nearly six decades of effort, there is a now the realistic prospect of imminent marketing submissions for vaccines against that elusive pathogen, respiratory syncytial virus (RSV).
RSV infection is a significant global healthcare burden, with the very young, the elderly, and the immunocompromised being at greatest risk of poor outcomes. An estimated 33 million recorded RSV episodes occurred globally in children aged 5 years and younger during 2019, with an associated hospitalisation rate of roughly 10%. Mortality risk was greatest in youngest infants (26,300 related in-hospital deaths in all children aged five years or less, with half of these deaths occurring in children aged six months or under)1. Taking a single Western European country perspective, RSV accounts for close to half a million general practitioner visits each year and some 34,000 hospitalisations in the United Kingdom2.
Adult hospitalisation rates vary greatly between low and high-income countries, with an estimated 2017 incidence rate of 13 or less hospitalizations per 100,000 adults over 65 years in Africa and Asia, to over 200 per 100,000 in the United States3. Following release from hospital, between 10-16% of American RSV patients still require professional nursing care4.
For most infants and adults, RSV is thankfully mild and self-limiting. Treatment for those hospitalised with severe symptoms comprises best standard of respiratory infection supportive care: there are no approved specific therapies for RSV infection. In the absence of prophylactic vaccination, Synagis® (palivizumab) a monoclonal antibody developed by Medimmune and approved in the late 90s still serves as a valuable preventative treatment in infants at highest risk of RSV. Another prophylactic antibody, Beyfortus® (nirsevimab: co-developed by AstraZeneca and Sanofi) recently received European marketing approval for the prevention of severe RSV infection in high-risk infants.
RSV drug development
RSV drug development has had its share of recent stumbles. Johnson & Johnson terminated late-stage clinical development of rilematovir in April this year, while Enanta Pharmaceuticals' EDP-938 failed to improve symptoms in a Phase II study involving low-risk adult patients. A handful of antiviral candidates remain in clinical development, with Ark Biopharmaceuticals posting positive Phase III data from a multi-centre paediatric study of an ex-Roche candidate, ziresovir, with the company hopeful of making an initial marketing submission in China. Pfizer, as a complement to its RSV vaccine ambitions, acquired Reviral and its early clinical stage antiviral portfolio for up to $525m in June this year.
RSV vaccine development has a long and somewhat notorious history. In the mid-1960s, a clinical study of a formalin-inactivated RSV was conducted in infants aged between two and seven months. Of those contracting RSV infection, 80% of vaccinated children experienced severe disease, compared with only 5% of infants in the control group: two vaccinated subjects died. The phenomenon of vaccine-related "enhanced respiratory disease" (ERD), while never fully explained, has been attributed to alterations in RSV protein antigens through formalin treatment, resulting in the production of non-neutralising antibodies. Subsequent in vivo studies suggest that multiple processes contribute to ERD5.
Cautious RSV vaccine development restarted in the 1970s, encompassing the gamut of then available technologies: live attenuated and chimeric vaccines; recombinant adenovirus vaccines encoding a variety of RSV antigens, and protein subunit vaccines. Hopes were pinned on the RSV F (fusion) protein as a vaccine candidate, being both immunogenic and highly conserved across A and B RSV subtypes. Like the SARS-COV-2 S (spike) protein, the purpose of the RSV F protein is to fuse with human cell membranes, undergoing a major conformational shift from "preF” to a more stable "postF" form in the process. Although immunogenic, the postF form failed to elicit antibodies capable of preventing infection in clinical studies, causing AstraZeneca to abandon its MEDI-7510 F protein candidate.
Antigen conformation is everything when it comes to RSV vaccine efficacy, a truth evidenced by the Phase III failure of Novavax's recombinant preF nanoparticle vaccine, The current crop of RSV vaccine candidates exploits the efforts of a US-China research collaboration which successfully developed a stabilized version of the preF protein capable of generating potent neutralizing antibodies6.
Stabilised preF vaccine candidates for older adults from Pfizer and GSK could reach the market within the next 12 months. In June, GSK announced that "statistically significant and clinically meaningful reductions" [in RSV infection rate] were observed in a 25,000 subject Phase III study in older adults (60 years plus) of its RSVPreF3 OA candidate. More colour was provided in an October 13th press release, with a claimed efficacy of close to 94% against severe RSV infection, and a similar level of protection observed in those over 70 years and in those with co-morbidities. Overall efficacy against RSV infection was 82.6%, with consistent protection across A and B subtypes7.
In August, Pfizer released top-line data (accrued from around 37,000 subjects) from the Phase III RENOIR study of its bivalent RSVpreF (PF-06928316) candidate in adults aged 60 years plus, indicating a vaccine efficacy against severe disease of 85.7%8. Differences in study endpoints confound direct comparison, and while the GSK candidate appears to the have the edge, both vaccines have successfully achieved meaningful levels of protection in older adults.
GSK and Pfizer are also pursuing maternal immunisation as a route to neonatal protection. Interim efficacy data from Pfizer’s 10,000 subject Phase III global MATISSE study indicates significant efficacy (81.6%) against severe disease requiring medical intervention through the first 90 days of life, with still substantial efficacy (69.4%) over a six-month follow-up period9. GSK’s programme suffered a setback in February 2022, with an undisclosed safety signal halting the 20,000 subject Phase III GRACE study and two smaller studies.
GSK looks set to take first honours in the RSV vaccine race, having secured priority review from the FDA, with a decision anticipated by May 3rd, 2023. This follows acceptance of a new drug review by Japanese regulators, and of a marketing authorization application by European Medicines Agency under accelerated assessment last month, with a decision on European approval expected in the third quarter of 2023.
Late-stage RSV vaccine pipeline
The GSK and Pfizer candidates head up an expanding late-stage RSV vaccine pipeline. Johnson & Johnson is enrolling older adults in a 27,500 subject Phase III study of a preF-encoding adenovirus vaccine, ad26 RSV preF, while Bavarian Nordic is recruiting 20,000 older adults in a Phase III study of its modified Vaccinia virus Ankara-BN® (MVA-RSV) candidate encoding five RSV antigens selected to stimulate both antibody and cellular immune responses. As of September, Moderna was two-thirds of the way towards a target enrolment of 34,000 older adults in a Phase III study of mRNA-1345.
How big is the prize? A much-cited SVB Leerink analyst estimate forecasts GSK and Pfizer roughly splitting annual revenues of $5 billion by 2030, with Johnson & Johnson, Moderna and others sharing a further $4 billion or so10. Sales in the older adult market segment alone could reach $5.2 billion by 2030.
Conclusion
RSV vaccine approval will be welcomed by an industry sector which, after the limelight of its COVID-19 successes, is keen to show that it has much to offer a post-pandemic world. The late-stage RSV vaccine pipeline showcases a diversity of approaches, and while not all contenders will reach market, the availability of an expanded range of enabling technologies bodes well for success in tackling recognised and future vaccine challenges.
Citations
1Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis. L Li Y et al. Lancet. 2022;399(10340):2047-2064.
2The burden of respiratory syncytial virus: Understanding impacts on the NHS, society, and economy. Fusco F et al. Santa Monica, CA: RAND Corporation, 2022. https://tinyurl.com/ye25at43.
3The burden of respiratory syncytial virus in adults: a systematic review and meta-analysis. Tin Tin Htar M et al Epidemiol Infect. 2020 Feb 13;148: e48.
4RSV-associated hospitalization in adults in the USA: A retrospective chart review investigating burden, management strategies, and outcomes. Walsh E et al. Health Sci Rep. 2022 Apr 14;5(3): e556.
5Unveiling integrated functional pathways leading to enhanced respiratory disease associated with inactivated respiratory syncytial viral vaccine. Russell MS et al Front Immunol. 2019 Mar 29; 10:597.
6Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. McLellan JS et al. Science. 2013 Nov 1;342(6158):592-8.
7GSK’s older adult respiratory syncytial virus (RSV) vaccine candidate shows 94.1% reduction in severe RSV disease and overall vaccine efficacy of 82.6% in pivotal trial. Company release, online 13th October 2022. https://tinyurl.com/ye2xrva3
8Pfizer announces positive top-line data from Phase 3 trial of older adults for its bivalent respiratory syncytial virus (RSV) vaccine candidate. Company release online 25th August 2022. https://tinyurl.com/mr2x3fyu
9Pfizer announces positive top-line data of Phase 3 global maternal immunization trial for its bivalent respiratory syncytial virus (RSV) Vaccine Candidate. Company release, online 1st November 2022. https://tinyurl.com/yck3xzuy
10GSK, Pfizer, and Johnson & Johnson race toward $10B-plus RSV vaccine market: analyst. Fierce Pharma online 8th September 2021. https://tinyurl.com/4ncfscpt