A Long-Awaited Vaccine

by Gertrud U. Rey

Almost sixty years have passed since the initial formalin-inactivated respiratory syncytial virus (RSV) vaccine caused enhanced disease in children when they were subsequently infected with the virus. Since then, RSV has continued to be a substantial public health threat to infants, young children, and older people. Although progress in developing a new vaccine has been slow and cluttered with setbacks, several recent breakthroughs have brought us not just one, but two promising new RSV vaccines.

The RSV fusion (F) protein is highly conserved between RSV A and B – the two major antigenic subtypes of human RSV. As its name implies, this protein mainly serves to mediate fusion between the viral particle and the host cell membrane, a process that induces the F protein to undergo a structural rearrangement from its pre-fusion conformation. Studies by Jason McLellan and colleagues have shown that the pre-fusion form of the RSV F protein is more immunogenic than its post-fusion form, an observation that inspired the development of vaccines consisting of purified F protein locked into its pre-fusion conformation. This otherwise unstable structure can be synthetically produced and maintained by insertion of two or more strategically placed copies of the amino acid proline, a structurally rigid molecule that can dramatically change the overall architecture of proteins.  

Based on the work done by McLellan, researchers at GlaxoSmithKline Biologicals developed Arexvy, an RSV vaccine that consists of a purified pre-fusion F protein. The composition is monovalent, meaning that it only contains the F protein of RSV subgroup A. The vaccine is made more immunogenic with addition of an adjuvant – a liposomal formulation that contains two immunostimulants: a derivative of lipopolysaccharide from Salmonella minnesota and a saponin molecule extracted from the bark of the South American evergreen tree Quillaja saponaria. The RSV F antigen and the adjuvant are supplied separately and combined prior to administration of the mixture as a single intramuscular injection. Phase III clinical trials engaging 25,000 adults over 60, and aimed to test the safety and efficacy of the vaccine, showed that Arexvy is safe and reduces the risk of severe RSV-associated lower respiratory tract disease by 94% compared to a placebo control vaccine. The FDA has already approved Arexvy for use in individuals aged 60 and older, and the vaccine is scheduled to be rolled out in advance of the 2023/2024 RSV season. Approval for use of Arexvy in pregnant individuals and children is expected later this year.   

Abrysvo is an alternative RSV vaccine formulation developed by Pfizer. This vaccine does not contain an adjuvant and is intended to be administered as a single intramuscular injection to pregnant individuals during the last trimester to protect their infants during the first six months of life. The composition is bivalent, meaning that it contains two copies of the pre-fusion F protein: one from RSV A and one from RSV B. Preliminary results from a phase III trial done in 7,400 pregnant individuals show that the efficacy of Abrysvo against severe RSV-induced lower respiratory tract illness is 82% during the first three months and 70% through the first six months of life. Although the trial is ongoing, the FDA Advisory Committee has already voted in support of approving Abrysvo for use in pregnant individuals, based on the positive safety and efficacy data obtained so far. A final decision with regard to full licensure is expected in August 2023.

The concept of using the pre-fusion structure of a viral glycoprotein as a more immunogenic form of an antigen in a vaccine is based on many years of research in the RSV field. The success in stabilizing the RSV F protein into its pre-fusion conformation motivated scientists to engineer similar amino acid changes into the Middle East respiratory syndrome coronavirus spike protein, which is also more immunogenic before it binds and fuses with the host cell membrane. When the COVID-19 pandemic started, scientists were able to apply the same strategy to stabilize the pre-fusion version of the spike protein of SARS-CoV-2, one of the factors that accelerated the path to a vaccine. This sequence of events accentuates the fact that science is not a linear process and highlights the importance of communication and collaboration among scientists to solve both old and new problems.

[Maternal immunization against RSV was discussed in a previous post. Abrysvo was approved for use in older adults on May 31, 2023 based on the results of a different phase III clinical trial done in 37,000 adults aged 60 years or older. The material in this blog post is also covered in Catch This Episode 47.]