Episode 329: Finally several successful Respiratory Syncytial Virus (RSV) vaccines available!
This episode is an update on the extensive analysis on RSV in Ep 302, which already discussed the problems and progress of vaccine development, but with only preliminary results.
I will first remind of the headlines of Ep 302 and then discuss the new information on successful trials, based on Eric Topol’s recent paper (Ep 329-1). So, clearly, Par 1 is a long introduction based on Ep 302 with some additional illustrations to bring everybody on the same page. The new information can be found in Par 2.
Par 1 “The long and winding road” to a safe and effective RSV vaccine
The field of vaccination has been hampered by an incident in the sixties with a formaline-inactivated (FI) vaccine that caused exacerbation of a subsequent infection.
The emphasis is on the development of vaccines for pregnant women, to provide newborns with maternal Ab and vaccination of elderly at increased risk.
It has taken till very recently before two candidate vaccines from Pfizer and GSK received authorization in the US.
In the meantime, passive immunotherapy with the monoclonal Palivizumab was the standard for at-risk young infants. Today there a few new mAbs such as Nirsevimab and Clesrovimab which are being approved
Ep 302-14: Killikelly Sc Rep 2016: Vaccine development against RSV in the sixties started with a disaster: enhanced respiratory disease (ERD) syndrome in originally seronegative children who received the formalin-inactivated (FI)-RSV vaccine.
A three dose regimen (0, 1, 4 months) was used in subjects between 2 and 7 months of age,
- 16 were hospitalized of the 20 infected children in the FI-RSV-vaccinated group (N = 31)
- compared to only 1 hospitalized of 21 infected in the control groups (N = 40)
The immunological basis:
- FI-RSV induced high titers of binding antibody with weak neutralizing and fusion-inhibitory activity: in the context of large viral antigen load led to immune complex deposition and complement activation in airways upon subsequent RSV infection.
See Ep 329-1: Delgado Nat Med 2009: Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease.
Fig from Ep 329-2: Julie Bigay Front Immunol 2022: Mechanisms of vaccine-enhanced disease
- Natural RSV infection after immunization with FI-RSV was associated with exaggerated peribronchiolar inflammation and infiltration of neutrophils and eosinophils into airways due to a Th2-biased immune responses and airway hypersensitivity characterized by up regulation of IL-4, IL-5, IL-13, and IgE.
Fig from Ep 329-2: Julie Bigay Front Immunol 2022: Mechanisms of vaccine-enhanced disease
- There are weak cytolytic T cell responses
Ep 302-12: Taylor
This is especially clear in neonates because of their immature immune system
- Neonatal CD4+ T cells are skewed towards Th2 and Treg development. Less differentiation towards Th1 due to reduced IL-12, coupled with increased Th1 apoptosis due to IL-4 signaling.
- Follicular helper CD4. T (Tfh )cells, while stimulated by IL-4 to differentiate, have arrested development, with generation of short-lived pre-Tfh cells.
- IL-4 signaling s also limits IL-17 production and skews the humoral response towards IgE production.
- Immaturity of B cell response Both neonatal Tfh and B cells have poor migration to germinal centers, which structurally demonstrate poor organization. B cells also have increased production of IL-10 and spontaneous secretion of IgM.
- CD8+ T cells show increased proliferation, generation of reactive oxygen species (ROS) and antimicrobial peptides (AMPs), BUT reduced cytotoxicity and memory formation.
The immune response to respiratory viruses in neonates
- The neonatal response favors a type II response, with increased IL-33, IL-25 and TSLP released from the epithelium, increased type 2 innate lymphoid cells (ILC2), increased type 2 helper T cells (Th2), and differentiation of M2-like alveolar macrophages (= rather suppressive)
- CD8 T cells have reduced T cell receptor (TCR) avidity, while both CD8 T cells and natural killer (NK) cells show reduced effector functions.
- Germinal center (GC) reactions are diminished in neonates, with less T follicular helper (Tfh) cell differentiation and less IgG production from GC B cells
Moreover, it was suggested that immunological priming with the FI-RSV vaccine was responsible for aberrant responses to subsequent Infection in infants with an immature immune system (with naturally poor Ab maturation capacity, weak CTLM function and skewing to Th2 -see .
However, there was no enhanced RSV disease when individuals are first primed with live virus infection or vaccinated with attenuated replication-competent vaccines given intranasally or parenterally
The suspected culprit is the F protein in the post-fusion conformation, as this is induced by formaldehyde inactivation (FI)
Ep 302-15: Mazur Lancet Infect Dis 2023 provides a very nice state-of-the-art
Because of the history with FI-RSV and the deleterious Th2 bias, an RSV vaccine for RSV-naive recipients ideally elicits potent neutralising antibodies without a Th2 bias.
Although a definitive correlate of protection against RSV infection remains elusive, but cell-mediated immunity, mucosal IgA and neutralising antibodies have been associated with protection.
Overview of present candidates
Par 2 The recent successful phase 3 trials
Ep 329-4: Graham Barney in NEJM Feb 2023 summarizes the rationale for the “prefusion F protein” as the basis for all new vaccines.
The Effect of Respiratory Syncytial Virus (RSV) Fusion Glycoprotein (F) Structure on Antigenicity.
The trimeric RSV F protein in its prefusion state (middle) is anchored on the viral envelope by a transmembrane domain at the Caboxy-terminus. At the apex of the prefusion F protein, there is an epitope (denoted in red) targeted by antibodies with high neutralizing activity.When F protein rearranges into the post-fusion form (left), either spontaneously on the viral membrane or after creating a fusion pore with the host cell membrane, this epitope is lost → no use ton include post fusion F in a vaccine
Stabilizing mutations can be introduced on the interior of the protein (right, small circled areas) to hold it in the prefusion conformation and preserve neutralization-sensitive epitopes at the apex for use as a vaccine antigen.
The ectodomain of RSV F vaccines can be delivered as a soluble trimeric protein (right) by constraining the Carboxy terminus
(right, large circled area) or, if expressed by gene delivery, the membrane of the protein can be anchored by retaining the transmembrane domain
Three successful trials in older individuals
Ep 329-5: Papi NEJM 16 Feb 2023: GSK RSVPreF3 OA (= AS01E-adjuvanted RSV prefusion F protein)
120 µg of the prefusion protein + AS01-adjuvanted formulations increased RSV-specific Th1 CD4+ T-cell frequencies in older adults to levels similar to those observed in young adults after vaccination
Almost 25,000 US subjects of 60 +, mainly from the community, not frail but many with co-morbidities followed during 6.7 months after ONE dose vaccine or placebo (see Table 1)
Main outcome: Vaccine efficacy was 94.1% against severe RSV-related lower respiratory tract disease
71.7% against RSV- related acute respiratory infection.
Subgroup analysis (Table 2)
- Equally effective against subtype A and B
- Similarly effective in older age groups up to 80 years, but lower in 80+ (only 33.8 %)
- Similarly effective in people with comorbidities, but much lower in frail individuals (only 15 %)
Ep 329-6: Walsh NEJM 5 April 2023: Pfizer RENOIR (RSV vaccine Efficacy study iN Older adults Immunized against RSV disease)
The vaccine is described as “bivalent prefusion F”, with equal amounts (60 µg) of subtype A and B. I could not find the source of adjuvant.
A total of 34,000 US and international subjects > 60 years (few over 80) many with comorbidities received ONE dose of vaccine or placebo (Table 1). Folloçw-up for 311 days (10 months)
Efficacy seems to be similar as with GSK (provided that the definition of “severe” disease is similar)
Subgroup analyses of the primary end points according to participant age group (60 to 69 years, 70 to 79 years, or ≥80 years) and risk status (no prespecified high-risk conditions or ≥1 prespecified high-risk condition) indicated similar vaccine efficacy across subgroups, with wide confidence intervals reflecting small subgroup sizes
Ep 329-7: Falsey 16 Feb 2023 Janssen Ad26.RSV.preF–RSV pre F protein (= Combined Ad26 expressing prefusion F and protein).
= smaller phase 2b study in less than 6000 adults of 65 +
Criteria for respiratory disease are the same as in Pfizer study
Panel A shows the efficacy of Ad26.RSV.preF–RSV preF protein vaccine for the prevention of reverse-transcriptase–polymerase chain reaction (RT-PCR)–confirmed RSV-mediated lower respiratory tract disease according to three different case definitions: three or more symptoms of lower respiratory tract infection (definition 1), two or more symptoms of lower respiratory tract infection (definition 2), and either two or more symptoms of lower respiratory tract infection or one or more symptoms of lower respiratory tract infection plus at least one systemic symptom (definition 3). Case definition 3 captured all RT-PCR–confirmed RSV-mediated acute respiratory infections in this trial.
One success to prevent infant severe RSV by vaccination of pregnant women
Ep 329-8: Kampmann NEJM 5 April 2023 Pfizer MATISSE Maternal Immunization Study for Safety and Efficacy
A worldwide phase 3 trial in pregnant (weeks 24-36) women IM administration of the same bivalent pre-fusion F protein as in RENOIR trial.
Primary endpoint = any OR severe medically attended lower respiratory RSV infection (confirmed with PCR)
- Respiration rate per minute : > 60 OR > 70 (infants < 2 months); > 50 OR > 60 ( at 2-12 months); > 40 OR > 50 ( 12-24 months)
- Oxygen saturation: For any lower resp: SpO2 < 85 %
For severe lower resp SpO2 of less than 93%, use of a high flow nasal cannula or mechanical ventilation, admission to an intensive care unit for more than 4 hours, or lack of response or unconsciousness
Reduction in severe medically attended RSV lower respiratory infection was significant.
CONCLUSIONS: The protein vaccines based on the prefusion F protein constitute a breakthrough in the long and winding road towards an effective vaccine against severe RSV in newborns and elderly.
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