WHAT HAPPENED
After languishing for decades, the world finally has access to highly effective vaccines that protect against respiratory syncytial virus (RSV), or rather against the development of its complications, which are often severe and therefore potentially life-threatening.
Currently, two RSV vaccines are available on the market: Arexvy and Abrysvo, developed by GlaxoSmithKline and Pfizer, respectively.
A third RSV vaccine is on the way: Moderna will soon offer mResvia.
Arexvy, Abrysvo, and mResvia vaccines are indicated for immunization of at-risk individuals to prevent RSV-associated acute respiratory disease (ARD) and lower respiratory tract disease (LRTD), including severe ones.
The RSV vaccines Arexvy, Abrysvo, and mResvia are administered once intramuscularly.
All three RSV vaccines, Arexvy, Abrysvo, and mResvia, have been approved for active immunization of individuals aged 60 years and older. Additionally, Abrysvo is authorized for vaccination of pregnant women (at 32–36 weeks of gestation) in order to provide newborns with passive immune RSV protection from birth to 6 months of age.
Arexvy has secured approvals from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in early May 2023 and early June 2023, respectively [1] [2].
Abrysvo debuted in the United States in late May 2023 to immunize the elderly, and then subsequently added pregnant women in late August of the same year [3] [4]. In Europe, the vaccine received marketing authorization simultaneously for these two indications in late August 2023 [5].
mResvia will be approved by the FDA and EMA very soon.
mResvia is the hypothetical brand name of Moderna’s RSV vaccine.
- The following brand names are on the list of potential ones for Moderna’s RSV vaccine: mResvtru, mResva, mResvy, mRisvi, mResiva, mResivi, mResivo, mResvia, mResvio, mResivio, mRisivio, mResvtek / mResvteq / mResviteq, mResyvaq, mResvivaks.
WHY IT MATTERS
Respiratory syncytial virus (RSV) is the etiological agent of acute respiratory disease (ARD) and lower respiratory tract disease (LRTD). The latter is associated with a severe course in at-risk groups, including infants, young children, and the elderly (60 years and older) [1]. This is particularly true for those who are debilitated or have comorbidities [2].
RSV-associated infections develop in approximately 3%–7% of elderly individuals in the United States and Europe [3] [4].
The severe course of LRTD can lead to exacerbation of underlying chronic diseases, hospitalization, and death [5] [3] [6] [7] [8]. Severe LRTD imposes a significant burden on the elderly, with 18% requiring intensive care, 31% requiring home health care after discharge, and 26% dying within one year of hospitalization [9]. The severity of LRTD is likely due to an aging immune system that is no longer able to produce a proper specific T cell response to RSV [10].
Statistics on RSV-associated infections in adults are underestimated because, unlike influenza, most countries do not require the collection of such data and RSV tests, which are not routine, may be unreliable [11] [12].
In 2019, approximately 5.2 million cases of RSV-associated infections were reported in high-income countries, resulting in 470,000 hospitalizations and 33,000 hospital-acquired deaths [13].
The morbidity and mortality associated with RSV are comparable to, and in some years even higher than, those associated with influenza. However, the vast majority of older adults are vaccinated against influenza [9] [14].
CHALLENGE
Virtually all adults are primed by respiratory syncytial virus (RSV) reinfections occurring throughout life. However, the immunity gained from this priming gradually declines as a result of immunosenescence, which is defined as an aging immune system [1].
The magnitude, composition, and functionality of innate and adaptive cell-mediated immune responses change under the influence of immunosenescence [2] [3]. With aging, naïve and IFN-γ-secreting RSV-specific T cells become less abundant and less functional, and bone marrow–derived naïve B cells decrease, underpinning the increased susceptibility of older adults to viral infection [1] [2] [3] [4] [5] [6] [7].
Despite the daunting burden of RSV-associated infections, the pharmaceutical industry has been unable to offer reliable prophylactic protection against respiratory syncytial virus for six decades straight. Without the benefit of hindsight, no one has been able to develop an effective and safe vaccine. Among the obstacles in the development of an RSV vaccine were the lack of an accurate correlate of protection and the low immunogenicity of vaccine candidates [8] [9].
An effective RSV vaccine should robustly recall or elicit humoral and cell-mediated immune responses. This can be achieved by boosting or inducing strong and persistent responses by neutralizing antibodies and restoring or inducing RSV-specific T cell responses [1].
HOW IT WORKS
All three respiratory syncytial virus (RSV) vaccines — Arexvy, Abrysvo, and mResvia — have selected the viral fusion protein F, the envelope glycoprotein of the virion, as their antigenic target. This protein is highly conserved in two subtypes of RSV, A and B, and is necessary for fusion of the pathogen with the host cell and subsequent infection. It is also crucial in the pathogenesis of RSV-associated infections [1] [2].
The RSV protein F exists in two primary conformational states: a metastable pre-fusion (PreF) and a stable post-fusion (PostF) state. The PreF state leads to the fusion of the virus and host cell membranes through a conformational change to the PostF state. The pre-fusion conformation of RSV protein F is the primary target of the natural immune response to RSV, displaying all the epitopes required for neutralizing antibody production, and eliciting a more enhanced response by neutralizing antibodies compared to its post-fusion conformation [3] [4] [5] [6] [7].
This is the rationale behind the design of RSV vaccines, which target PreF. Neutralizing antibodies generated by the immune system after immunization bind to PreF, thereby locking the F protein and blocking virus entry into the cell.
Arexvy (codenamed RSVPreF3 OA, GSK3844766A) by GlaxoSmithKline is a subunit vaccine that includes recombinant PreF protein (120 μg) derived from the amino acid sequence of RSV strain A2, and is backed by a proprietary adjuvant, AS01E, combining 3-O-desacyl-4′-monophosphoryl lipid A (MPL) from Salmonella minnesota and a saponin (QS-21) purified from plant extract Quillaja saponaria and encapsulated in a liposomal formulation.
Abrysvo (codenamed RSVpreF, PF-06928316) by Pfizer is a bivalent subunit vaccine that is formulated with two recombinant PreF proteins (60 µg each) derived from the amino acid sequences of RSV serotypes A and B. No adjuvant is used.
Both Arexvy and Abrysvo are supplied in a lyophilized (dried) form, necessitating their reconstitution by dilution with complete sterile water prior to direct vaccination.
mResvia (codenamed mRNA-1345) by Moderna is a set of mRNA instructions encoding PreF encapsulated in lipid nanoparticles. Once the mRNA instructions have been delivered to cells and processed, the cells begin to express the RSV antigen on their surface, which then stimulates an immune response.
In contrast to Arexvy and Abrysvo, mResvia is provided in the form of pre-filled syringes, which affords users a more convenient administration method.
Arexvy, Abrysvo, or mResvia: Which RSV Vaccine Is Better?
Large-scale clinical trials have reliably confirmed the protective efficacy of the RSV vaccines Arexvy, Abrysvo, and mResvia, which are administered intramuscularly in a single dose.
For a clear understanding of the level of efficacy of this trio of vaccines, their clinical results are summarized in the table.
Comparative efficacy of the RSV vaccines Arexvy, Abrysvo and mResvia
More to follow…
BIG MONEY
Industry estimates indicate that the market value of the respiratory syncytial virus (RSV) vaccine is approximately $10 billion.
In the partial (two-quarter) debut year of 2023, Arexvy and Abrysvo generated revenues of 1,238 million pounds ($1,535 million) and $890 million, respectively (primarily in the U.S.). These figures serve to substantiate the viability of the RSV vaccine business.
Going forward, sales of RSV vaccines are expected to grow rapidly, entering new markets and expanding the eligible population, including at-risk individuals 18 years and older.
PATENT WAR
In June 2022, Pfizer initiated legal proceedings in a British court, challenging the validity and requesting revocation of three GlaxoSmithKline patents in Europe relating to respiratory syncytial virus (RSV) vaccine technology. In January and March 2023, similar suits were filed in courts in the Netherlands and Belgium. In response, GlaxoSmithKline filed counterclaims, asserting that Pfizer’s RSV vaccine infringes its patents.
In August 2023, GlaxoSmithKlein went to a U.S. court, claiming that Pfizer had infringed four patents related to components of the RSV vaccine. Then, in November 2023, two more patents were added to the suit.
A decision on the UK suit is expected by the end of the second quarter of 2024. In the Netherlands, the second-instance hearing took place in March 2024. In Belgium, the first-instance decision is scheduled in the first quarter of 2025. Patent litigation in the U.S. has not yet commenced.
In any case, GlaxoSmithKlein is seeking monetary compensation from Pfizer, in addition to a ban on the sale of the competitor’s RSV vaccine.