3am Today

I received an email this morning asking me about how vaccines are made and are they safe. My first thought was to reply to the email with website links to WHO and CDC’s websites, but quickly realized after reading those websites and a bunch of others, why I was being ask the question in the first place and that there needed to be a more specific answer with more information than the normal buzz of how it works.

To the email sender, a big thank you as I got to learn something – a lot of somethings to be exact – new today and to everyone else, keep those emails coming in. Hit that contact link in the top right or if you’re on a mobile device, hit that menu button in the top right.

First. I thought I was done writing about anything related to COVID back in September (hit that search box and type in COVID to see the rest of the post about it), but it would appear that I would be wrong since there is mention of the COVID situation in this writing. My hope is the next time that I write about it, it will be a piece on the past tense history of it.

On to the good stuff. How is a vaccine made. No matter what the vaccine is, whether it be for a bad year of influenza (which COVID is a family member of) or any of the other multitudes of vaccines that had been made and for the most part, are still being made and stored in case of another out-break of whatever the vaccine was made for.

Vaccines have greatly enhanced our ability to save lives, giving us control, elimination, or near-elimination of many life-threatening diseases. The path to disease prevention is the development of a novel (new) vaccine and is a complex and lengthy process that generally takes 10 to 15 years. As to be expected, COVID is a major out-break, hence, scientist and pharmaceutical companies around the world have been in major overdrive to come up with a solution or a vaccine that can be distributed as quickly as possible to get this out-break brought under some kind of control.

In the US, there are six initial steps needed to create a vaccine. The obvious first would be to identify what the virus is as I wrote about in The New Normal – Part Two

After the discovery of what it is, then comes the part of finding out what makes it tick. After all of the mountain of data and the spinning eyes of the scientist involved has been compiled, then it is off to the next six steps.

Step 1: Exploratory and Research Usually, laboratory research is conducted for 2 to 5 years to identify antigens to include in a vaccine.
Step 2: Preclinical and Safety & Efficacy Researchers conduct testing to assess vaccine candidates, immunogenicity, their ability to elicit the desired immune response. Other areas of focus include short-term toxicology, formulation, and development of a scalable, efficient, and reproducible manufacturing process. This data collection and analysis can take around 2 years.

Step 3: Clinical and Safety & Efficacy in Humans In the US, an application for an Investigational New Drug (IND) is submitted to the U.S. Food and Drug Administration (FDA). Only with an approval of the IND by the FDA does the potential vaccine proceed through 3 phases of testing in humans.

Phase 1 (2 years) – Typically, less than 100 volunteers are administered the candidate vaccine in a non-blinded study to determine whether it is safe to proceed to Phase 2, and to determine whether a sufficient immune response is provoked.

Phase 2 (2 to 3 years) – A larger group of subjects receive the vaccine candidate; the safety, immunogenicity, doses, immunization schedules, and delivery methods are studied.

Phase 3 (5 to 10 years) – This randomized, placebo-controlled, blinded pivotal study generally involves thousands of people in whom vaccine safety and efficacy are tested. This trial generally includes monitoring potential side effects in subjects, determining whether the vaccine candidate can help to prevent disease, and testing whether it leads to the production of antibodies against the specific pathogen.

Step 4: Regulatory Review & Approval – Licensing If the candidate vaccine is determined to be safe and effective, a Biologics License Application (BLA) is submitted to the FDA, which may conduct its own testing. The FDA also inspects the production of the vaccine candidate and monitors its potency, safety, and purity; this entire process could take up to 2 years.

Step 5: Production – Scaling Up Manufacturing scales up production of large quantities of the vaccine, ensuring all product meets the necessary regulatory requirements, including current Good Manufacturing Processes (cGMP)

Step 6: Quality Control – Performance Review, Post-Marketing The vaccine is continuously tracked and monitored for its performance, safety, and effectiveness through pharmacovigilance conducted after the product is released into the market.

As you can imagine, because of the severity of this out-break, the time frames mentioned above have kinda been thrown out of the window in an effort to get this virus under control. While the principals and testing will always be the same due to the sensitive nature of the way the human body works, the time frames have been short as much as possible.

To try to answer this next question, we’re going to venture into an unknown, but a very widely and most of the time, a very wildly topic of discussion. Is it safe? The quick answer is yes and no. To find out why, you have to look at what is in a vaccine and why it makes some people sick, while others carry-out their day whistling their favor song.

There are many parts to a vaccine and it doesn’t stop at what is in the vial, it also has to do with what the vial that the vaccine came in is made of. You might be thinking uhhh glass dummy. Yes, but not quite.

A refresher about your immune system. The first time your body encounters a germ, it can take several days for your body to produce the army of proteins (and some other things too) needed fight the infection and get that army to the front-lines to kill the infection. After the infection is over, your body’s immune system keeps a few memory cells that remember what it learned about how to protect against that disease.

If your body encounters the same virus or bacteria again, it will produce antibodies to attack the germ more quickly and efficiently. In theory, this works wonderfully, but what happens if the virus mutates, spawns itself off as a new virus to fool the immune system.

That is one of the major problems with COVID-19. In some cases, it has been found that it can generate or mutate into another strain, hence why the media has been saying that we are all gonna die and further inciting panic by telling the public that the scientist or this or that politician is not doing anything about the virus problem. The media in and of itself has been more of a problem than the virus itself. Well, almost anyway, but you get what I’m referring to.
Moving right along. There are several components of a vaccine.

1. There is the antigen that has been made to replicate what your immune system will make and send to where the virus is hiding-out in your body. Only in rare cases is the antigen kept at full strength (something like the bubonic plague would be a good example). For the most part, the antigen is diluted significantly during the manufacturing process or is diluted just before the needle goes into you arm.

2. There is a stabilizer that is mixed in with the antigen. This is there to keep the antigen for separating and clumping. If you’ve ever spilled sugar on the counter and got it wet, you know that it clumps. This holds true for millions of things in our lives that we never give a second thought of. It also keeps the antigen for sticking to the glass of the vial.

3. There is a preservative mixed in with the rest of it and more often than not, this is what makes people feel ill for a few days to a week after getting the shot. Preservatives are also in millions of products that we use or are in our home as we speak. The preservative in this case is a six-membered ring with two heteroatoms, and their fused carbocyclic derivatives. You didn’t think you were going to get off easy in today’s class, did ya?

2-Phenoxyethanol is widely used in vaccines. Cyclization of phenoxyethanols 203, in the presence of (diacetoxyiodo) benzene and iodine, gave a mixture of 1,4-benzodioxane 13 and 6-iodo-1,4-benzodioxane 204 via alkoxy radicals (Equation 36).

Then, nucleophilic aromatic substitution was applied for the synthesis of 1,2,4,6,7,9-hexafluoro-1,4-dibenzodioxin from 2,3,4,6-tetrafluorophenol in the presence of sodium t-butylate. In a similar way, cyano-1,4-dibenzodioxins and cyano-1,4-dibenzodithiins have been synthesized by fluorine displacement reactions with catechols. In accordance with a similar mechanism, the synthesis of spiro (1,4-benzodioxin-2,4?-piperidines) 205 and spiro (1,4-benzodioxin-2,3?-pyrrolidines) 206 have been developed from alcohols 207 and 208, respectively, both of them being obtained from 2-fluorophenol 210 with the corresponding epoxide 209 (Scheme 18).
Did you just skip that part? I don’t blame you, but I put it there in case any of you wanted to geek-out on how it’s made.

Vaccines administered from multi-dose vials generate several concerns, including contamination risk and potential for waste. PCV13 formulated with 2-phenoxyethanol, a preservative used in other pediatric vaccines, allows expanded vaccine delivery in resource limited settings while meeting strict WHO requirements for antimicrobial suppression. A Phase 3, open-label, randomized controlled trial in Gambian infants assigned participants to receive PCV13 at ages 2, 3, and 4 months from either a multi-dose vial containing 2-phenoxyethanol (n = 245) or a standard single dose syringe (n = 244). Non-inferior immunogenicity of the multi-dose vial formulation was demonstrated for all serotypes according to IgG titers and opsonophagocytic assay. Local and systemic AEs following vaccination were mostly mild and comparable between groups. Local reactions occurred approximately 24-hours post-vaccination and resolved by 72 hours. No participant reported a severe local reaction. Fever rates were low (1.2%-3.6%) and comparable between groups, and no occurrences of fever > 40.0C were recorded.

Last, but not least and very important as mentioned above, the vials that the vaccine come in.

Borosilicate glass is not like your normal pickle jar or beer bottle, it is still made of sand in a simple term, but the sand is processed differently. Borosilicate glass contains the following properties by mass: Silicon dioxide (SiO2) 80.8%, Boron oxide (B2O3) 12.56%, Sodium oxide (Na2O) 3.98% and Aluminum oxide (Al2O3) 2.28%. It also has smaller amounts of chlorine, as well as oxides of iron, titanium, zirconium, calcium, magnesium, and potassium.

Borosilicate glass originated from the German chemist and glassmaker Friedrich Otto Schott, who invented it in 1897. The company he founded, Schott AG, continues to produce Fiolax borosilicate glass for pharmaceutical uses. Schott and other companies manufacture 50 billion borosilicate glass containers each year to bring vaccines and other medical products to patients.

Like the soda-lime glass found in windowpanes or food and beverage containers, borosilicate glass is made primarily from silicon dioxide, the main constituent of sand. But soda-lime glass contains proportionally more sodium oxide, which is derived from sodium carbonate, also called soda ash and more calcium oxide, which originates from calcium carbonate limestone. Borosilicate glass has added boron oxide and other compounds that help stabilize the glass.

Borosilicate glass is a chemically inert material and remains unchanged under all normal environmental circumstances. It is stable and retains its shape at temperatures as high as 500C and as low as 0 C. These properties allow borosilicate vials to store drugs safely and prevent contamination.

Pharmaceutical products really need to interact as little as possible with the packaging. Shifts in pH introduced by packaging can speed up degradation of delicate active ingredients. Metals or other contaminants can leach out of vials or other packaging materials, such as elastomer seals on tiny bottles. For some products, the migration of boron from vials can speed up degradation, meaning that borosilicate glass isn’t the best packaging material for them.

Borosilicate glass can’t rest on its laurels. Corning, maker of the popular Pyrex borosilicate glassware, and other companies are crafting medical vials made from novel materials. They say these materials resist the process of delamination, in which thin bits of glass flake or spall-off the interior. The tiny chips of glass can interact with the ingredients in a vial, leading to drug degradation.

Regardless of the materials they use for medical vials, manufact urers across the globe are stepping up output to meet demand for packaging COVID-19 vaccines. DWK Life Sciences announced earlier this month that it was expanding and modernizing its facility in Tennessee to double production capacity for its borosilicate glass vials. The company makes products with brand names familiar to those working in laboratories. Duran, Wheaton, and Kimble.

Meanwhile, Italy’s Stevanato Group inked a deal in June with the Coalition for Epidemic Preparedness Innovations (CEPI) to supply 100 million borosilicate glass vials. Each will hold 20 doses of a COVID-19 vaccine. CEPI, a partnership founded in 2017 to develop vaccines for future epidemics, has formed a coalition with the World Health Organization (WHO) and the global vaccine alliance Gavi. The coalition, called Covax, intends to distribute 2 billion doses of a COVID-19 vaccine by the end of 2021.

I’m sure we can all agree on one thing. We just want it to be over with.