By P. Ashley Wackym, MD, FACS, FAAP
Chair, Medical and Scientific Advisory Board, Vestibular Disorders Association
Professor and Chair, Department of Otolaryngology – Head and Neck Surgery, Rutgers Robert Wood Johnson Medical School
This Covid-19 (SARS-Co-V2) pandemic has had an unparalleled impact on the world, our health, our businesses, our mental health, our families, and our lives during 2020, and now in 2021.
Fortunately, due to the unique government, business sector, military, research community, and pharmaceutical industry collaboration assembled through Operation Warp Speed, we now have two vaccines currently available (Pfizer/BioNTech and Moderna), and two more vaccines likely available in the near future (Johnson & Johnson and Oxford/AstroZeneca). The availability of these vaccines was facilitated by the U.S. Food and Drug Administration.
Unfortunately, doubts about the safety about these vaccines have been sown, which must be dispelled. This will be addressed later.
It should also be noted that there is emerging evidence that Covid-19 can cause hearing and balance problems as a consequence of infection. More about this will be included in another update, but is another reason that you should be vaccinated.
The Basics of Our Immune System
Let me start with a little background about how our immune systems work. Immune cells in our body are designed to attack anything that is foreign to us. If the immune system sees a protein, virus or bacteria that it recognizes as foreign it will launch an attack.
If it is fighting a virus, or the spike protein on the surface of the Covid-19 virus, as described shortly, it needs time to build up the full attack. The immune system decides what parts of the virus to attack and it then ramps up production of what it needs to attack those parts, which can take days. Meanwhile the virus is still replicating (reproducing) and infecting more cells. Once the immune system fights off the virus it will remember the virus using memory cells (more on this later). If that virus enters our body again, the memory cells recognize it and use their previous experience to attack and eliminate the virus before it can make us sick.
Vaccines create the attack strategy and memory without us actually getting infected by the virus. The Covid-19 vaccines prepare our body to stop the virus before we can get sick.
The Four New Vaccines
These four new vaccines use a new and unique strategy for producing immunity to Covid-19 (for comparison, descriptions of other common vaccination strategies will be outlined below). The general outline of this strategy used in the messenger ribonucleic acid (mRNA) vaccine is to get our body’s cell machinery to make the target protein and to prime our immune system attack and neutralize the “spike protein” – the protein on the surface of the virus that is the key which unlocks the Covid-19 virus entry into our cells. If the Covid-19 virus cannot get into our cells there can be no infection, complex illness, has no after effects (sequelae) of infection.
How Do These Vaccines Work?
There are four main steps to how this type of vaccine works.
First, there needs to be an “envelope” that protects the mRNA sequence from its injection into our bodies at the vaccination site to our cell membranes and across them into our cells. Next, once the freed mRNA (which carries the instructions for how the cell will make the Covid-19 spike protein) is inside our cells it uses existing cell machinery, which naturally makes all the other proteins in our cells once various mRNAs are delivered to this machinery. The protein production machinery then synthesizes the designed conserved Covid-19 spike protein. Once this foreign protein is “seen” by our body, our immune system kicks in to produce the protective mechanisms required for our body to clear the Covid-19 virus without producing infection. The first time our body encounters this Covid-19 spike protein as manufactured from the vaccine’s mRNA, it requires several days to make and use all the virus-fighting tools needed to get over the infection. After the exposure to the synthesized spike protein, the immune system remembers what it learned about how to protect our body against that disease. The body keeps a few immune memory cells (T-lymphocytes) that go into action quickly if the body again encounters the spike protein – this time on newly introduced Covid-19 viruses from exposed infectious human carriers (people). When the familiar antigens (the spike protein) are detected — this time from an actual Covid-19 virus exposure — B-lymphocytes produce antibodies to attack them again.
Are These Vaccines Safe?
Some have expressed concern that all of these vaccines were produced too quickly and they are not safe. As outlined below, all of the steps required to develop this vaccine strategy and make the specific vaccine occurred over a 35 year timeline! With the clinical trials for these vaccines there are three phases that build upon one another:
- Phase I: Is the treatment safe?
- Phase II: Does the treatment work?
- Phase III: Is the treatment better than what is available?
With vaccine trials, 60 days of monitoring during Phase III is required – but 90 days of monitoring was performed during the Covid-19 mRNA-based vaccine Phase III trials, reflecting the fact that the results were not compromised nor the trials rushed.
I received the first dose of the Pfizer Covid-19 vaccine on December 17, 2020. Personally, I had one symptom that I always experience after a shot – tenderness at the injection site for two days. Many of my colleagues here at the Rutgers Robert Wood Johnson Medical School and others across the country and internationally have affirmed the same or similar experience.
These mRNA Vaccine Strategies are New but Not that New
While applications of these strategies are relatively new, the Covid-19 mRNA-based vaccines are not the first ones applied to people. Human trials of cancer vaccines using the same mRNA technology have been taking place since 2011. If there was a major problem with the mRNA-based technology, we would have seen it before now.
The Development of the mRNA-Based Covid-19 Vaccines
The story about how the building blocks assembled to create this novel strategy is interesting because they evolved in parallel pathways and for different purposes, but were pulled together to create these novel vaccines.
Dr. Katalin Karikó is a scientist who, in 1985, first started working to develop a strategy to use mRNA molecules, the building blocks and genetic template to induce our body to produce a specific protein. The problem was that when mRNA is introduced into our body our immune system destroys it before the protein can be made. This problem was overcome two decades after she immigrated to the United States from Hungary when, in 2005, she published the solution she developed with an immunologist, Dr. Drew Weissman, while they were working at the University of Pennsylvania. Another important component is how to protect and deliver the mRNA into our body’s cells. Dr. Robert Langer, a biomedical engineering professor at the Massachusetts Institute of Technology and a co-founder of Moderna, was an early pioneer into developing these technologies.
Another important contribution needed to develop these new vaccines was made by the research team of Barney Graham, MD, PhD. Dr. Graham is the Deputy Director of the NIAID Vaccine Research Center of the National Institute of Health (NIH). He was my Chief Resident in Medicine when I was a medical student at Vanderbilt University School of Medicine – a brilliant person. One problem with viruses is that they change frequently, or mutate, to evade their host’s eliminating or preventing their ability to infect us and for them to flourish. These changes with coronaviruses were studied by Dr. Graham to better understand what parts of the spike protein are conserved, or do not change. It was this discovery that was used to design the mRNA sequence used in these Covid-19 mRNA-based vaccines.
The Johnson & Johnson and Oxford/AstroZeneca strategies use the principle of depending on your cell machinery, but get the code for the Covid-19 spike protein into the cells in a different way. Both of these vaccines use adenovirus as the vector (like a Trojan horse) to get the instructions of how to make the spike protein inside of our cells. Adenoviruses are a family of viruses that have dozens, maybe hundreds, of members. Most do not cause any known disease, or they only cause mild “common cold”-like symptoms. Scientists developed a way to use strains of adenoviruses that do not cause disease as a delivery system for vaccines. So, one benign virus is used to deliver the vaccine against a malicious virus, Covid-19. The gene for the Covid-19 spike protein that we want the immune system to respond to is inserted into the adenovirus genome as DNA. Then the person to be vaccinated against Covid-19 is infected with this harmless adenovirus. When the adenovirus gets into your cells the DNA is turned into mRNA, causing the cells to make the vaccine spike proteins, which triggers the immune response. When these adenovirus vaccines are developed, the design of the vector also removes genes from the adenovirus so that it cannot replicate (reproduce) in the vaccinated person. This is done as an added safety measure.
With these major advances, the pharmaceutical industry was able to develop slightly different vaccine strategies, conduct the clinical trials to prove safety and efficacy, actualize massive vaccine production for the world, and now provide these vaccines to help eliminate Covid-19.
What Other Strategies are Used to Create Vaccines?
Since most of you have had vaccines before, I would like to provide information about other types of vaccines, so the differences with the new mRNA vaccines can be better understood.
Typically, the best way to induce an immune response against a particular virus is to be naturally infected. Assuming that you survive the infection – and that you can tolerate the permanent after effects, which can occasionally be severe – immunity is often complete and long lasting. The second best way to aquire a protective immune response is to be immunized with a live, weakened (attenuated) form of the virus (such as Zostavax [vaccine for shingles]). The third best way is to use just one part of the virus (called subunit vaccines, this was the strategy employed by Shingrix [best vaccine for shingles]). Because they are not as good as live, weakened viral vaccines, subunit vaccines invariably require adjuvants to help boost immunity. Currently, there are four main types of vaccines that infants, young children and adults commonly receive in the United States.
Live Attenuated Vaccines. Live attenuated vaccines induce your immune system to fight viruses and bacteria. These vaccines contain a version of the living virus or bacteria that has been weakened so that it does not cause serious disease in people with healthy immune systems. Because live, attenuated vaccines are the closest thing to a natural infection, they are good teachers for the immune system. Examples of live, attenuated vaccines include measles, mumps, and rubella vaccine (MMR) and the herpes varicella zoster (chickenpox) vaccine Zostavax. A live attenuated influenza (flu) vaccine (FluMist Quadrivalent) is approved for people 2 through 49 years of age and is delivered into the nose. Even though they are very effective, not everyone can receive these vaccines. For example, individuals with weakened immune systems, for example, those who are undergoing chemotherapy, or autoimmunity patients treated with steroids or biologics suppressing immune function, or people with HIV infections, cannot get live vaccines.
Inactivated Vaccines. Inactivated vaccines also fight viruses and bacteria. These vaccines are made by inactivating, or killing, the self-replicating infectious units during the process of making the vaccine. The inactivated polio vaccine is an example of this type of vaccine. Inactivated vaccines produce immune responses in different ways than live, attenuated vaccines. Often, multiple doses are necessary to build up and/or maintain immunity. The majority of annual influenza (flu) vaccine are an inactivated vaccine based upon the best “guess” about what strains will dominate the flu season each year.
Subunit Vaccines. Subunit vaccines include only parts of the virus or bacteria, or subunits, instead of the entire virus or bacteria. Because these vaccines contain only the essential antigens and not all the other molecules that make up the self-replicating infectious units, side effects are less common. The pertussis (whooping cough) component of the DTaP (Diphtheria, tetanus, and pertussis) vaccine is an example of a subunit vaccine. Another example of a subunit vaccine is Shingrix for the herpes varicella zoster virus – the reactivated latent virus throughout our body responsible for shingles and thought to be commonly associated with sudden hearing loss and vestibular neuronitis. All individuals in the United States age 50 or above should receive this vaccine, particularly patients with vestibular disorders. Shingrix is more effective than Zostavax – but why is that? The answer lies in an adjuvant that has never been used in the United States until now. It is called QS-21. The “QS” stands for Quillaja saponaria. Otherwise known as the soap bark tree, Quillaja saponaria is native to the country of Chile. Using a highly purified product derived from the tree’s bark (the 21st chromatographic peak in the purification process), researchers have now been able to do something that had once been considered impossible; dramatically boost an immune response which has been weakened because of age (senescent) and therefore less robust. QS-21 is currently being studied for its capacity to enhance immune responses against influenza, malaria, hepatitis B virus, human papillomavirus, HIV, and tuberculosis vaccines as well as immunological strategies against lung cancer and malignant melanoma. Another important subunit vaccine is Gardasil-9 which should be given to everyone between the ages of 9 and 46 years. This vaccine is targeted to 9 of the human papilloma virus (HPV) serotypes and is the only vaccine that can prevent cancer. Men’s HPV+ oral-pharyngeal cancer has now eclipsed women’s HPV+ cancer in rate of occurrence and both could be eliminated from vaccination.
Conjugate Vaccines. Conjugate vaccines fight a different type of bacteria. These bacteria have antigens with an outer coating of sugar-like substances called polysaccharides. This type of coating disguises the antigen, making it hard for a young child’s immature immune system to recognize it and respond to it. Conjugate vaccines are effective for these types of bacteria because they connect (or conjugate) the polysaccharides to antigens that the immune system responds to very well. This linkage helps the immature immune system react to the coating and develop an immune response. An example of this type of vaccine is the Haemophilus influenzae type B (Hib) vaccine, which helps prevent ear infections.
This Covid-19 (SARS-Co-V2) pandemic has had an unparalleled impact on us. Fortunately, there are two and soon to be four new vaccines available for producing immunity to Covid-19. While applications of these mRNA-based vaccine strategies are relatively new, the Covid-19 mRNA-based vaccines are not the first ones applied to people and have been used since 2011. They are safe and effective. I received my Covid-19 vaccination and you should too.