May 21, 2024

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7 vs 4: FDA expert committee votes to approve Pfizer’s RSV vaccine

7 vs 4: FDA expert committee votes to approve Pfizer’s RSV vaccine



 

7 vs 4: FDA expert committee votes to approve Pfizer’s RSV vaccine.

On February 28, 2023, Pfizer announced that an FDA expert committee supported FDA approval of its RSV vaccine . The FDA has until May 2023 to make a final decision.

 

7 vs 4: FDA expert committee votes to approve Pfizer's RSV vaccine

The FDA expert committee voted 7:4 to approve the safety of its RSV vaccine and 7:4 to approve the effectiveness of its RSV vaccine.

 

7 vs 4: FDA expert committee votes to approve Pfizer's RSV vaccine

 

At present, GlaxoSmithKline and Moderna’s RSV vaccine phase III clinical trials have also been successful, and GlaxoSmithKline’s RSV vaccine has the highest protection rate. However, in pregnant women, only the Pfizer RSV vaccine has achieved phase III clinical success.

 

Previously, Barney Graham, former deputy director of the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases in the United States, introduced the RSV vaccine development process and the principle of designing vaccines based on protein structure in the NEJM “Viewpoint” column .

The team led by Graham played a key role in the development of the mRNA COVID-19 vaccine in cooperation with Moderna. He pointed out that the RSV vaccine design provided important guidance for the rapid development of the mRNA COVID-19 vaccine.

 

The success achieved with structure-based RSV vaccine design guided a rapid response to the Covid-19 outbreak. Middle East respiratory syndrome coronavirus outbreak during analysis of RSV preF structure.

At the time, we did not know the atomic-level structure of any coronavirus protein, but over the next few years, the structure of the spike protein was resolved and the stabilizing effect of maintaining the prefusion spike conformation and increasing protein expression levels was finally identified. mutation.

These studies are the foundation of the COVID-19 preparedness plan, including public-private and academic collaborations that already existed in 2019.

Decades of work required for RSV research were compressed into weeks in SARS-CoV-2 research thanks to advances in biomedical technology and the RSV blueprint, yielding the sequences, structures and antigens needed to rapidly develop safe and effective vaccines and therapeutic mAbs .

 

The researchers conducted five phase 3 trials using the postfusion conformation F protein, which is known to be the target of neutralizing antibodies.

Two trials used proteins of viral origin and three were based on recombinant proteins, one of which was produced in insect cells and two of which were produced in Chinese hamster ovary cells.

None of these candidate vaccines increased neutralizing activity by more than 5-fold, and field trials failed to meet the primary efficacy goal.

In vitro studies by Melero and colleagues suggest that antibodies specific for prefusion F (preF) may be responsible for most of the neutralizing activity in serum.

Collectively, these studies suggest that the structure of the F protein may be a key factor in RSV antigenicity.

 

Wiley and colleagues solved the first atomic-level structure of influenza hemagglutinin, a class I fusion protein, in 1981.

Hemagglutinin remains relatively stable in the prefusion conformation until exposed to low pH, whereas the trimeric fusion proteins of most other enveloped viruses are in a metastable state until published by Lamb and colleagues in 2006.

Atomic level structure of the viral F protein in the prefusion conformation.

Shortly thereafter, the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases (NIAID) initiated a research project aimed at determining the atomic-level structure of the RSV F protein, starting with individual epitopes and eventually the complete postfusion F (postF) and preF structure.

 

Obtaining RSV preF crystals is difficult because the unmodified and unbound protein spontaneously rearranges into a highly stable postfusion conformation (see illustration).

Therefore, to obtain the desired prefusion trimer conformation, both ends of the molecule must be constrained.

Finally, the trimerization domain foldon from the T4 phage fibritin protein was used for the C-terminal domain, while an antibody Fab fragment, which can form a complex by binding to the tip of preF, was used to stabilize the trimer.

These antibodies were identified by screening monoclonal antibodies (mAbs) that neutralize the virus but do not bind postF.

 

Influence of Fusion Glycoprotein (F) Structure of Respiratory Syncytial Virus (RSV) on Antigenicity

The trimeric RSV F protein in the prefusion conformation (middle) is anchored to the viral envelope by the C-terminal transmembrane domain.

There is an epitope (red) targeted by a high neutralizing antibody on the top of the pre-fusion F protein.

After the F protein rearranges (either spontaneously on the viral membrane or after forming a fusion pore with the host cell membrane) into a postfusion conformation (left), the epitope disappears.

Stabilizing mutations (small circle area on the right) can be introduced into the protein to maintain the pre-fusion conformation and retain the apical neutralization sensitive epitope as a vaccine antigen.

The ectodomain of the RSV F vaccine can be delivered as a soluble trimeric protein (right) by restricting the C-terminus (large circle on the right); if expressed intracellularly by gene delivery, it can be anchored by retaining the transmembrane domain .

 

One of the mAbs was discovered by screening hybridomas in immunized mice, and the other two human mAbs were discovered in proprietary databases, initially by Beaumont and colleagues using an unbiased approach to expand peripheral blood memory B cell clones Discover.

The three-dimensional structure of RSV preF was determined using human mAb D25. mAb D25 is the precursor to the potent nirsevimab, which has been shown to prevent severe RSV disease within 150 days when given at birth.

Thus, resolution of the RSV preF structure revealed a novel site of vulnerability and neutralization sensitivity, suggesting its potential as a target for vaccine development efforts.

 

Mutations that introduce disulfide bonds and fill the cavity stabilize F in the preF conformation. Studies have found that proline substitutions and other mutations can also stabilize preF.

Using preF as a reagent allowed for detailed mapping of the antigenic surface in all conformations of the F protein, determining the contribution of each epitope to neutralizing virus, and isolating hundreds of new human monoclonal antibodies.

Immune responses to RSV are composed of epitope-specific repertoires and B-cell phenotypes, and we demonstrate that antibodies that bind preF alone have greater neutralizing potency than antibodies that bind both preF and postF.

Later, studies have shown that preF is more immunogenic than postF in enhancing RSV neutralizing activity, and several studies have shown that preF is effective when used as a vaccine for pregnant women or the elderly.

Decades of application of new technologies to basic RSV research have provided us with the knowledge of virology and pathogenesis needed to design and evaluate effective vaccines.

 

The Covid-19 vaccine has now been approved for clinical use, and the RSV vaccine has been proven effective and awaits approval.

So far, we have entered the era of precise antigen design based on protein engineering guided by atomic-level structure.

Hopefully, these advances lead us to successfully address the unmet medical needs and threats posed by new pathogens in the future.

 

 

 

7 vs 4: FDA expert committee votes to approve Pfizer’s RSV vaccine

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