The Next Billion Dollar Vaccine Deal, Part 1

RSV vaccines for adults

With revenues falling precipitously from sales of Covid19 drugs and jabs, it’s time for pharma to crank up the vaccine machine with a new market driver: vaccines for RSV. The three new shots were released almost at the same time for babies and adults, and an RSV vaccine for pregnant women is soon to be approved.  

What is RSV?

Respiratory syncytial (sin-SISH-uhl) virus, or RSV, is a common respiratory virus that usually causes mild, cold-like symptoms. According to the CDC, RSV is the most common cause of bronchiolitis (inflammation of the small airways in the lung) and pneumonia (infection of the lungs) in children less than 1 year of age in the United States. In fact, RSV is SO common that almost all children will have had an RSV infection – and acquired natural immunity - by the time they are 2 years old.

RSV vaccine in adults

RSV in adults usually include a mild cough, runny nose, sore throat, fatigue and rarely a fever. Adults over the age of 65 or those with health complications are at higher risk for developing more severe RSV. Most infections are mild, no different than a common cold, with symptoms resolving in less than two weeks.

Adults with COPD, have immunosuppressive illnesses, or have had bone marrow transplants have a higher risk of developing a more serious infection that may require hospitalization.  In the US, an estimated 150,000 adults 65 and older are hospitalized each year with RSV, and an estimated 10,000 may die from complications of this infection.

It can be difficult to know the difference between influenza A or B, COVID-19 and RSV infections because they have similar symptoms. For example, fever is more common in those with flu and COVID-19 but is uncommon with RSV. If you develop symptoms and want to know if you have one of these infections, LabCorp offers an at-home collection kit. A single nasal swab can be sent to the lab, with the results returned in about 2 days. If this may be of interest to you, it is best to have a kit on hand prior to the winter season to save time.

A big summer for RSV vaccines

May 3,2023

The FDA approved Arexvy, by GSK, for adults 60 years of age and older.

The ingredients in this shot should be enough for everyone to say, “No thank you” and investigate other ways to stay well during the winter months.

                                           

It took many years to characterize the 11 proteins within RSV. It has been determined that the surface F-protein is what binds to the host’s mucous membranes. Previous efforts to develop an RSV vaccine have faced several challenges, including the rapidly changing structure of the F protein on the viral surface. The vaccine manufacturers have found a way to stabilize glycoprotein F in its pre-fusion conformation (RSVPreF3).

This methodology is described this way:

The F-protein presents two different conformations, a lollipop-shaped pre-fusion (preF) form that is on the surface of the virus. After the protein interfaces with the cell membrane, it flips to a crutch-shaped post-fusion (postF) state. The two forms are antigenically distinct, and both have been considered as potential vaccine candidates.  However, the preF form has been shown to induce the majority of highly neutralizing antibodies following natural infection, making this the antigen of choice for vaccine development.

Arexvy is distributed with two vials which must be mixed together before injected. One vial contains the powdered antigen; the other is the fluid suspension containing the adjuvant.

The RSVPreF3 antigen is created by culturing it with Chinese Hamster Ovary cells. The antigen is then separated from the cells by filtration and then formulated with excipients. Interestingly, the excipients mixed with the antigen are not listed on the package insert.

Excipients are ingredients that are used in product formulations and include adjuvants, stabilizers, and preservatives. Common excipients present in vaccine preparations include antibiotics, formaldehyde, aluminum, thimerosal, 2-phenoxyethanol, gelatin, sucrose, lactose, yeast, and bovine serum. A table of excipients can be found here.

The second vial is the solution containing the adjuvant, ASO1e, which is a modified form of one of four proprietary adjuvants developed by GSK (formerly GlaskoSmithKline) in the mid-1980s. AS01 is composed of mono-phosphoryl lipid A, (known as MPL), QS-21 and liposomes. AS01 is used to stimulate the innate immune response by binding to TLR4 (Toll-like Receptor 4).  

• MPL is derived from cell wall of a Salmonella bacteria. A very powerful stimulator of the immune system, MPL actively binds to and stimulates TLR4, leading to the production of pro-inflammatory cytokines. AS01e use 3D-MPL, a synthetic version of MPL. 3D-MPL has been designed to mimic the immune-stimulating properties of MPL while potentially improving upon its efficacy.        

• QS21 is extract made from the bark of a South American tree, Quillaja saponaria. It is highly reactogenic and can only be used when combined with other MPL and liposomes.

• Liposomes are artificial vesicles that have a liquid core, surrounded by one or more phospholipid layers, such as cholesterol and phosphatidylcholine.

Another ingredient in Arexvy is trehalose, a naturally occurring disaccharide (sugar) that is widely used in the biopharmaceutical, food, and cosmetic industries due to its stabilizing and cryoprotective properties. The abstract of a 25-page paper published by American Chemical Society in 2022, Synthesis and Application of Trehalose Materials, describes trehalose this way:

Over the years, scientists have developed methodologies to synthesize linear polymers with trehalose units either in the polymer backbone or as pendant groups...  

Additionally, numerous reports have focused on the synthesis and formulation of materials based on trehalose, such as nanoparticles, hydrogels, and thermoset networks.

Among many applications, these polymers and materials have been used as protein stabilizers, as gene delivery systems, and to prevent amyloid aggregate formation. In this Perspective, recent developments in the synthesis and application of trehalose-based linear polymers, hydrogels, and nanomaterials are discussed, with a focus on utilization in the biomedical field.                                      

When the two vials are mixed together (reconstituted) each 0.5cc dose contains:

• RSVPreF3 antigen                   120 mcg

• MPL                                             25 mcg

• QS-21  from (tree bark)              25 mcg

• Trehalose                              14,700 mcg

• Sodium Chloride (salt)         4,400 mcg

• Potassium dihydrogen phosphate 830 mcg

• Dipotassium phosphate           260 mcg

• Polysorbate 80                        180 mcg

• Disodium phosphate anhydrous 150 mcg

• DOPC (lipids in lysosome)      500 mcg

• Cholesterol                                125 mcg

Each dose also contains hamster ovary cells and hamster DNA...and of course, like every other vaccine, Arexvy has not been evaluated for carcinogenic or mutagenic potential. Since this is targeted for adults over 60 years of age, apparently this is not important.

If you can believe the stats from the three clinical trials, Arexvy is said to be 83% effective in preventing cases of lower respiratory infection caused by RSV infection.

What about side effects?

The FDA is loosely monitoring for serious side effects. Generally, this is a requirement to have a place on the GSK for self-reporting reactions. Do patients know about this? Do they know where to find it?

The FDA said it is requiring GSK to monitor for signs of Guillain-Barré syndrome,   a nerve disorder that can cause paralysis or weakness. It is also requiring ongoing research into the risk of developing acute disseminated encephalomyelitis (ADEM), a neurological disorder characterized by swelling in the brain and spinal cord that damages myelin. Myelin is the whitish protective coating over nerves that helps with electrical nerve signaling. The FDA says two people in the clinical trials for the vaccine developed the condition after getting the RSV shot with an influenza vaccine.

May 31,2023

A few weeks later, the FDA approved a second RSV vaccine for adults. Abrysvo, by Pfizer, is also indicated for adults 60 years of age and older. There are two major antigenic subtypes of human RSV (A and B).

These two subtypes co-circulate during the same season and it has been concluded through a large, prospective, multicenter, multiyear U.S. study of hospitalized children with bronchiolitis, there was no difference in clinical severity between children with RSV-A and RSV-B. Studies have similarly found no difference in severity between RSV-A and RSV-B in adults.

Given those findings, it is unclear with Pfizer chose to make its RSV vaccine using antigens from both subtypes A and B.

Similar to Arexvy, Abrysovo must be reconstituted by mixing together its antigens, recombinant RSVPreF A and RSVPreF B, with an accompanying vial of sterile water. When ready to be injected, the vaccine contains:

• RSV PreF-A antigen                60 mcg

• RSV PreF-B antigen                60 mcg

• Polysorbate 80                          80 mcg

• Sodium chloride (salt)         1,100 mcg

• Sucrose   (sugar)                 11,300 mcg       

• Mannitol (sugar)                22,500 mcg

• Tromethamine**                      110 mcg

• Tromethamine HCl              1,040 mcg

Each dose also contains residual hamster cells and hamster DNA

**Tromethamine and tromethamine hydrochloride are ingredients called buffers. They are added to vaccines so they can be stored for longer at higher temperatures.

The ingredients in these shots should be enough for everyone to say, “No thank you” and investigate other ways to stay well during the winter months.

Of course, Pfizer and GSK have said they expect a multibillion-dollar market for RSV vaccines. And Pfizer is counting on these new vaccines to help offset declining revenue from its COVID-19 products.

Will we fall for more ‘vaccination nation’ tactics or do simple, common-sense things instead:

• Cover your coughs and sneezes with a tissue or your upper shirt sleeve, not your hands

• Wash your hands often with soap and water for at least 20 seconds

• Avoid close contact, such as kissing, shaking hands, and sharing cups and eating utensils, with others if your ill. And stay home until you are well again.  

• Clean touched surfaces such as doorknobs and mobile devices frequently

• Regularly take your supplements: OptiMune - which has Vitamin D, Vitamin C, zinc, quercetin and N-acetyl cysteine (NAC) - all in one convenient capsule.

• As an adult, keep Opti-Vitamin D 50,000 IU and Opti-Vira Relief in your cupboard to stop any viral infection in its track when symptoms start.

Next week: RSV vaccines for infants and pregnant women.

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