Ensilica. Reducing the Cost of Pneumonia Vaccines by 90%.
Pneumonia is a disease where an infection, caused by organisms such as bacteria, viruses, and fungi, inflame your air sacs in one or both lungs, causing them to fill with fluid, or pus, leading to coughing with phlegm or pus, fever, chills, and/or difficulty breathing. (Mayo Clinic)
In 2017, Pneumonia killed just over 2.5 million people, 800,000 of which were children under the age of 5. That’s one child, every 39 seconds, making it the leading cause of child mortality. (Our World in Data & WHO & UNICEF)
The largest concentrations of death from pneumonia exist in countries with the lowest ability to pay for vaccines.
The three reasons Pneumonia is such a large problem is because:
1) Environmental factors such as undernutrition, air pollution, overcrowding, among other external factors create breeding grounds for bacteria and air particles. These stimuli can damage your lungs and can weaken your immune system making people highly prone to Pneumonia.
2) Vaccines are too expensive for families to afford. Even with the help of organizations like Gavi, who acquires and distributed vaccines at reduced prices ($3.05 USD per dose), the price to vaccinate kids in families of 3–5 kids remains a threshold that is difficult for many families. Additionally, Gavi initiatives, specific to Pneumonia, remain underfunded, despite their hopeful visions for the coming years.
In this article, my partner and I are going to specifically focus on a way we have identified that could significantly decrease the costs associated with the Pneumonia vaccines (specifically, PCV13), in hopes of making it that much more accessible. A study by The Lancet in 2019 estimates that global use of PVC13 or the Pneumonia vaccine could save roughly 400 million children annually. (The Lancet)
An Introduction to Conjugate Vaccine Immunology
PCV13 is structured as a conjugate vaccine to create immunity from a specific bacterium known as Streptococcus pneumoniae. Conjugate vaccines typically work by connecting some kind of protein (usually an antigen from the targeted bacteria) to a polysaccharide (usually a sugar), with a buffer, among other ingredients, to make a vaccine that can be effectively injected into an animal. The antigens provoke the immune system — while the conjugate (sugar) is used for a functional purpose (such as improving solubility).
S. pneumoniae is the bacterium responsible for most cases of pneumonia. PCV13 takes the 13 of the most common stereotypes of S. pneumoniae (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, 18C, and 23F) and conjugates their antigens to a nontoxic variant of diphtheria toxin known as CRM197. (CDC)
There are different variations of the Pneumonia vaccine, ranging from PCV3 (which covers 3 strains of S. pneumoniae) to PPSV23 (which covers 23 different strains and is slightly different in structure). PCV13 is known to be the most effective for the least amount of money and practical for the widest age range — making it the ideal candidate to engineer our solution around.
Breaking Down the Cost
The two largest contributors to the cost of getting vaccines from production, injected into a person, are cold chain infrastructure and hiring people to deliver the vaccines.
Cold Chain Infrastructure essentially means keeping the vaccines refrigerated at a temperature of 2–8° C so the proteins in the vaccine do not denature (unfold). Creating such infrastructure has been historically costly and can amount to anywhere from 40–80% of the costs of getting the vaccines produced and safely into people.
Hiring people for labor accounts for an additional 30–40% of costs. This includes transportation structure and delivery as well as paying people on the ground to be trained and hired to administer the vaccine to locals in countries. (WHO x PATH — Senegal, ChemistryWorld)
How We can Engineer Around Costs
Making Vaccines Stable at Higher Temperatures
Recently, there has been the successful release of a study regarding a process known as Ensilication. Ensilication is effectively a process by which nano-cages are built around proteins, containing them so that they physically can not unfold at higher temperatures. This has been successful with the Tetanus Toxin C-fragment (TTCF)in the diphtheria, tetanus and pertussis vaccine (DTP), a different type of conjugate vaccine, and has shown promising results in both a lab setting (Chen, YC., Smith, T., Hicks, R, 2017) and in Mice Trials (Doekhie, A., Dattani, R., Chen, 2019).
The output of the process of Ensilication is a powder that can be stored at higher temperatures and a wider variety of pressures, such as on an airplane, without the proteins denaturing. In one specific study by the University of Bath, Before administration of the compound, the powder is mixed with a saline compound to remove the silica from around the vaccine and create a serum that can be injected with a syringe. This process effectively eliminates the need for cold chain expenses because it puts the vaccine in a form that is stable without refrigeration.
Assumptions Made Through Ensilication
In attempting to replicate this process with the Pnemunia vaccine, it is important to recognize key differences between PCV13 and DTP. One key difference between the vaccines is that DTP vaccine uses a toxoid from Clostridium tetani (the tetanus bacteria) which is meant to mimic the effects of an antigen, while PCV13 directly uses antigens from the various strains of S. pneumoniae. This means that the proteins used in the two vaccines are different in what they’re made of, so they may react to the process of ensilication differently.
Another difference worth noting is that the two vaccines are structured differently. DTP is a few different vaccines bonded together while PCV is a mixture of different individual types of antigens bonded to sugars. The way DTP is structured is such that the only addition to the conjugations between the antigens is a capsular polysaccharide (a very hydrated [95%] molecule). PCV13 is structured using antigens conjugated to a protein called CRM197. CRM197 is a non-toxic mutant of diphtheria toxin — essentially a different type of method that is used as a delivery mechanism.
That said, we believe these are okay assumptions because toxoids are supposed to mimic the effects of an antigen while CRM197 is supposed to mimic the effect of alternative conjugations. We expect that the two should behave similarly under given conditions. While we do believe this warrants further investigation, we measure it as a minor assumption in our thought process.
Turning a Powder into a PIll💊
Given that the output of densification is a powder, our idea is, instead of just using the compound as a storage mechanism, we should be able to compress the compound into the form of a pill. This way, the vaccine could be ingested instead of being injected (removing a large chunk of the costs associated with labor, since you no longer need someone to administer the vaccine).
To understand how a vaccine might be administered as a pill we can look to how pills generally work in the body. Typically, swallowing medication such as a painkiller will fall down your throat and esophagus before being broken down by stomach acids among other things in the gastrointestinal tract, and then is absorbed into the bloodstream. Absorption can happen at any number of access points including the mouth of the large intestine, the small intestine, or after being processed through the liver. (Orlando Clinic Research Center, 2016)
Traditional delivery mechanisms to deliver pharmaceuticals use organic materials, such as cellulose, to protect the medication from the stomach and the stomach for the medication. This functions, and it functions well, but it’s also an added layer of complexity we don’t think is necessary.
As an alternative, we propose use silica as a carrier through the GI tract to a point of entry in the bloodstream, at which point the vaccine can be released.
Silica (which creates the nanostructure in ensilication) is commonly used as a binding agent in both food and drugs. It is also “Generally Recognized As Safe (GRAS)” by the U. S. Food and Drug Administration (FDA). Silica also happens to have a considerable amount of research into using it as a delivery mechanism. (Jafari, S., Derakhshankhah, H., Alaei, L., Fattahi, A., Varnamkhasti, B. S., & Saboury, A. A. (2019), Theobald, N. (2020), Pudło, W., Borys, P., Huszcza, G., Staniak, A., & Zakrzewska, R. (2019))
The way we propose using silica as a delivery mechanism is through a structure called (Hierarchical) Mesoporous silica nanostructures or MSNs. (Eur J Pharm Biopharm (2019), Biomed Pharmacother, (2019))
A mesoporous material is any material containing pores with diameters between 2 and 50 nm. The part about hierarchical refers to the structure — having smaller pores towards the center of the pill and larger pores towards the outside.
The actual chemical in these silica structures, surprisingly, isn’t actually silica- it’s a chemical called Tetraethyl orthosilicate or TEOS. TEOS can be assembled in various structures, such as the ones below, that emphasize properties making it very good for drug delivery.
MSNs, specifically, have a remarkably high level of chemical stability, high drug loading capacity, rigid framework, well-defined pores, easily controllable morphology, tunable surface chemistry, and high biocompatibility because of the Surface Area:Volume ratio. Essentially, this means MSNs are easy to manipulate and very good at what we want them to do — making them an ideal candidate.
The way this structure works is by creating TEOS nanocages that assemble around proteins, which then break away when hit with the right stimulus.
Through a process called functionalization, we can design add silica such that a certain factor can be used as the stimulus that determines when the vaccine will release. Investigation has been done into light, electrical (redox), chemical (pH), ultrasound, enzyme, temperature, antibody-antigen reaction, and glucose-responsive triggered drug release. Successful applications make these nanostructures useful systems for a variety of controlled-release applications. (Karishma T Mody, Amirali Popat, Donna Mahony, Antonino S Cavallaro, Chengzhong Yu, Neena Mitter, (2013))
We propose using a pH triggered release system for the pill for three reasons:
- There has been significantly more research done into pH-triggered responses — meaning we have less ambiguity if something doesn’t work how we expect it to.
- pH-triggered releases have higher delivery efficiency than alternative methods. (Ida Stefania Carino, Luigi Pasqua, Flaviano Testa, Rosario Aiello, Francesco Puoci, Francesca Iemma, Nevio Picci, 2007)
- Intracellular (within the body)features are favorable when trying to deliver something to the bloodstream. (Ida Stefania Carino, Luigi Pasqua, Flaviano Testa, Rosario Aiello, Francesco Puoci, Francesca Iemma, Nevio Picci, 2007)
What this should end up looking like is a typical pill. On a molecular level, it will be our ensilicated vaccine wrapped in additional layers of silica. The added layers of silica will somewhat resemble a dishwashing sponge. Each layer will have a unique structure, pore count, pore size, and thickness, meticulously calibrated to react in coordination with each change in the environment.
A diagram of the GI tract which the pill will pass through.
The pill will start by being swallowed at the mouth, then pass through the esophagus, and enter the stomach. Once in the stomach, the first protective layer of MSN will react with the acidity of the stomach. By the end of passing through the stomach, the first layer will be completely worn off, exposing the second layer to be processed through the pancreas. Once passed through the pancreas, the vaccine will have a final thin layer to protect it just long enough before it dissolves into the bloodstream at the mouth of the large intestine.
Once in the bloodstream, we expect the vaccine will function like any other traditional conjugate vaccine. The antigen will provoke the immune system to create a defense mechanism against the bacterium while the conjugate acts as a catalyst for the process.
Challenges That May Arise in Silica Delivery Systems
With any scientific finding comes potential challenges we anticipate will happen. In testing this process, we are concerned with 3 key things.
- The well-defined porous structures and corresponding large surface area of MSNs are quite beneficial for accelerating the degradation of MSNs. However, the chemical stability of MSNs is generally higher than that of organic Drug Delivery Systems (DDSs), which leaves a big bio-safety issue for their in vivo translations.
- It is difficult to detect the complex degradation process of MSNs in vivo because in vivo presence of both degraded species of MSNs makes it difficult to distinguish the exact amount of degraded products from the total detected amount. This means it is difficult to get separate how much of the delivery system was disassembled vs just spit out having never been processed a valuable data point.
- In vivo evaluations tend to exhibit unexpected results due to the complicated physiological environment. For example, the opsonization of Nanoparticles in vivo, transportation of Nanoparticles in bloodstream, enhanced permeability and retention (EPR) effect, etc., are difficult to imitate in vitro. This means it’s difficult to simulate how various scenarios might go in-vitro (outside the body).
Now that we have a thorough understanding of these processes, we can tie them back into the big picture idea of how this works.
A Brief Re-Cap
Pneumonia kills a lot of people each year. The reason we can’t get the vaccine. to people is because the price of infrastructure is too high. The two biggest costs are cold chain and paying people to administer the vaccine. Through ensilication, we can stabilize the vaccine at higher temperatures and odder pressures to handle environments outside of the cold chain. By turning this ensilicated material into a pill, we remove almost any costs associated with the administration of the vaccine.
So let me paint you a picture, best-case scenario, we reduce the costs by 90% — saving millions of people annually.
Worst case scenario, we still reduce the cost 50%, saving at least 400,000 children under the age of 5Best case scenario where — we reduce the costs 90% — saving millions of people annually.
Worst case scenario, we can still reduce the cost 50%, saving 400,000 children under the age of 5, and creating a foundational stepping stone in the world to engineering better vaccines.
We believe in a future where someone’s health isn’t limited by their geography. We call it ensilica.
Thank you for reading to the end, and we hope to make this idea a reality very soon.
— Satvik Agnihotri
Ensilica’s website: https://bit.ly/2RjusJD
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Hey Everyone,
My name is Satvik. I’m a 16-year-old interested in Machine Learning, Brain-Computer-Interfaces, and philosophy. Feel free to contact me on any of the platforms below. I hope you enjoyed the article!
Email: satvikagnihotri12@gmail.com
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