Antibodies. mRNA. Variants. These are just a few of the terms that have been etched into the pages of an ever-evolving pandemic dictionary over the past year.
As the United States approaches nearly 174 million vaccine doses administered, and people 16 and older have recently become eligible for the shot in Connecticut, Google searches for “vaccine” and related terms have reached an all-time high.
The News spoke to experts at the Yale School of Public Health, Yale's Department of Molecular, Cellular and Developmental Biology, the Yale New Haven Health system and the Yale School of Medicine to assemble a glossary of relevant terms, debunk some widely circulated myths and answer some of the most common and pressing questions about COVID-19 vaccines.
Molecular Keywords
Spike Protein
The coronavirus spike protein has been a central figure in much of the COVID-19-related scientific literature since the beginning of the pandemic. The spike protein is the key structure that enables the virus to enter human cells and wreak havoc — many studies have centered on the molecular mechanisms that permit the protein to do so, as well as on how mutations in this protein can lead to more transmissible SARS-CoV-2 variants.
“The spike protein is the protein situated on the surface of the SARS-CoV-2 virus,” said Albert Ko, chair of the Epidemiology Department at YSPH. “It’s important for many different reasons. The first is because … it’s the part of the virus that interacts directly with the host [cell].”
Ko explained that mutations in the genes that code for the spike protein can play a crucial role in affecting the transmissibility of COVID-19. Notably, the spike protein is the target for "protective immune responses" of many of the vaccines, Ko explained, specifically the mRNA vaccines such as Pfizer and Moderna.
ACE-2 Receptor
Short for “angiotensin-converting enzyme 2,” the ACE-2 receptor is the protein on the surface of many human cell types that interacts with the spike protein of SARS-CoV-2, Ko explained.
The spike protein of SARS-CoV-2 binds to the ACE-2 receptors, similar to how a key slides into a lock. The receptors act as a microscopic doorway that permits the virus to penetrate and infect host cells in the body.
Vaccine-Related Terminology
The Immunobiological Premise of Vaccines
Assistant professor of laboratory medicine and immunobiology Ellen Foxman explained that when a person is infected by a pathogen, memory cells within the immune system make sure that the body “remembers” that foreign substance, in case it ever has to fight that pathogen again. It can take weeks for one’s body to reach its maximal immune response to a foreign pathogen that it has not encountered before. But the immune system can immediately recognize and respond to a pathogen with which it has had prior exposure.
“A vaccine … [tricks] your body into thinking that it’s seen a bad virus already,” said Foxman. “The bottom line of what those vaccines are doing is tricking your immune system into thinking that it’s already seen the COVID virus, so that if you’re ever exposed, those defenses will protect you from the minute you’re exposed as opposed to having to wait a couple of weeks."
As Foxman described, this process of mounting an immune response is the reason why vaccines take a couple of weeks to reach their peak effectiveness in one’s body.
During the window of time between receiving a shot and developing full-fledged immunity, it is possible for people to get COVID-19, according to the CDC. But this does not mean that the vaccine does not work — just that it is still in the process of preparing one’s body to fight against the coronavirus.
But the prospect of becoming infected with COVID-19 after vaccination seems highly unlikely. A study published in The New England Journal of Medicine by scientists at the University of California San Diego School of Medicine and the David Geffen School of Medicine looked at COVID-19 risk in health care workers who had received either one or two doses of the vaccine between Dec. 16, 2020, and Feb. 9, 2021. They found that the absolute risk of becoming infected with COVID-19 after vaccination hovered at approximately 1 percent.
mRNA vaccines
When the coronavirus infiltrates the body, it hijacks cells and uses their internal machinery to replicate itself. This process, along with the ensuing physiological responses it triggers, makes the host sick, professor of molecular, cellular and developmental biology Paula Kavathas explained.
The mRNA vaccines for COVID-19 — notably Pfizer and Moderna — work by making neutralizing antibodies that bind to the spike protein on the surface of the SARS-CoV-2 virus to prevent it from latching onto and infecting host cells in one’s body.
The central dogma of molecular biology is that DNA makes RNA and RNA makes proteins. RNA is a set of instructions that can be translated from DNA on how to make the protein. Some vaccines inject foreign protein into the host’s body via an attenuated or dead virus. The mRNA vaccines, on the other hand, inject just the RNA — or the instructions — in order for one’s body to produce the foreign protein that will trick the body into thinking it has been exposed to the pathogen.
“The idea is that the RNA is made, and it’s surrounded with a lipid nanoparticle [in a vaccine],” Kavathas said. “That lipid nanoparticle can penetrate into your cells and the RNA is released into the cytoplasm, where it is then read by the host machinery and translated into protein."
Through this mechanism, the host’s cells are deceived into making several copies of a given protein belonging to the specific pathogen, Kavathas explained. This is exactly what would happen if a person were to be naturally infected with a virus such as SARS-CoV-2, but without the risk of becoming seriously ill, according to Kavathas.
"Our antigen presenting cells will take up this material and present it to our immune T cells and also our B cells will be able to bind the foreign protein and we can then make antibodies,” Kavathas added.
Booster Shot
The Moderna and Pfizer COVID-19 vaccines both require two doses in order to be maximally efficacious. The second dose is known as a “booster shot.” These shots generate more antibodies and more immune T and B cells than the initial dose, Kavathas explained.
Kavathas pointed out that the antibodies one gets from a second dose strengthen the initial antibodies produced by the body through somatic hypermutation. In this process, mutations are generated at a fast rate in the V region of B cells, which differentiate B cells that produce higher affinity antibodies. Higher affinity antibodies bind more strongly to the surface of an antigen. There tend to be more side effects from the booster shot because there are already memory cells and some antibodies present in the host to combat what the body perceives as a foreign pathogen, according to Kavathas.
Viral Vector Vaccine
A viral vector is a tool used frequently in biology as a carrier capable of delivering genetic material into host cells. Over the course of evolution, viruses have developed mechanisms to pass through a cell’s membrane and transport their genome into the targeted cell. Once inside the cell, a viral vector can co-opt the host cell’s molecular machinery and cellular processes to synthesize viral particles.
Viral vector vaccines, such as those developed by Johnson & Johnson and AstraZeneca, are “vaccines where components of the coronavirus are inserted into attenuated viruses — viruses that don’t cause disease or adverse reactions,” Ko said. “These attenuated viruses deliver components of the SARS-CoV-2 virus that … elicit an immune response.”
Specifically, components of SARS-CoV-2, such as the genomic sequence encoding the spike protein, are inserted into the genome of a different, non-harmful virus — the vector — which can then transport this information to the host cell, said Ko.
Though the viral vector itself is incapable of causing disease, it enables the body’s cells to produce spike proteins –– which are also incapable of causing disease when produced by the body in this manner, according to the CDC. The presence of this spike protein inside the body subsequently induces immune cells to learn how to make antibodies that can target the spike protein if that person is later infected by SARS-CoV-2.
The CDC emphasizes that viral vectors do not cause infection with COVID-19, nor do they cause infection with the virus used as the vector. Additionally, the CDC states that the “genetic material delivered by the viral vector does not integrate into a person’s DNA.”
Ko pointed to the Johnson & Johnson COVID-19 vaccine as an example of a viral vector vaccine that uses a human adenovirus as a vessel for the SARS-CoV-2 spike protein gene. This adenovirus itself is not harmful to humans and incapable of causing disease, he explained. Similarly, Ko described that the AstraZeneca coronavirus vaccine uses a chimpanzee's adenovirus, which is not harmful to humans, as its vector.
Adjuvant
An adjuvant is a substance that enhances or influences the immune system’s response to a vaccine, according to Foxman. RNA, for example, is a natural adjuvant.
Because most vaccines contain such a small amount of genetic information from the actual virus, with some containing only the synthetic genetic code for one of its proteins, the adjuvant helps to ensure that the body's immune system is stimulated enough to provide long-lasting immunity, according to the CDC.
Other adjuvants include aluminum salts, which are present in some coronavirus vaccine candidates — but not any of the FDA-authorized vaccines. Adjuvants have been used to help strengthen the immune response to various vaccines for over a century. Though it remains unclear how exactly aluminum salts could help promote a more robust immune response, the COVID-19 vaccine candidates that contained it produced high concentrations of neutralizing antibodies, according to a paper published in Nature Reviews.
Reactogenicity
As explained in a review published in Nature in January, vaccine reactogenicity "refers to a subset of inflammatory reactions that occur soon after vaccination." This is the body's immediate physical response to the chemicals that have been injected into it.
Reactogenicity is something that scientists closely examine to establish whether or not a vaccine is in fact safe to inject into people. While some symptoms — like local muscle soreness, headaches or fatigue — might be well-tolerated and even expected for some vaccines, the severity of potential side effects has to be evaluated before approval of vaccine candidates.
Vaccine Distribution
Cold Chain
Cold chain refers to a supply chain that is temperature-controlled.
Ko explained that the Pfizer vaccine must be kept at temperatures between -80 to -60 degrees Celsius— ultra-frigid conditions that are colder than the average annual temperature in Antarctica. In the case of the Moderna vaccine, typical freezer temperatures of -25 to -15 degrees Celsius suffice. Finally, “the J&J and the AstraZeneca [vaccines] can be pretty much distributed and refrigerated at 4 degrees [Celsius] … what we have at home [on the] bottom part of the freezer or refrigerator,” Ko said.
Requirements for sub-zero storage and distribution temperatures pose problems for the vaccine rollout in lower- and middle-income countries. Ko emphasized that this is not a new challenge. Delivery of polio and measles vaccines in electricity-deficient settings of sub-Saharan Africa, Latin America and Asia historically presented huge obstacles to distribution efforts. Ko noted this was one of the reasons the World Health Organization established the Expanded Program in Immunization in 1974. One of the program's goals was to improve cold chain infrastructure in under-resourced settings.
“Because of [cold chain requirements], Pfizer and Moderna [vaccines] are probably not going to be game changers in those more resource-limited settings because of the need for those ultra-low temperature freezers,” Ko said.
Vaccine Approval
Vaccine vs. Vaccine Candidate
When the pandemic first hit, several pharmaceutical companies across the world began their pursuit for a viable COVID-19 vaccine — one that was safe and effective in conferring immunity against the coronavirus.
As each independent group of scientists and companies conducted their tests, the vaccines were referred to as "candidates." This is because there had not yet been formal approval for these vaccines to be widely distributed.
“Usually what happens is vaccines are developed and go through several stages of what we call proof of concept,” Ko said. “These are both preclinical as well as clinical [phases and tests]. Then they get licensed. Until they get licensed, we call them candidates. Once they’re licensed, we call them vaccines.”
Ko explained that in the current pandemic, Emergency Use Authorization granted by the Food and Drug Administration marks the transition point from a COVID-19 vaccine candidate to COVID-19 vaccine.
Emergency Use Authorization
Emergency Use Authorization, or EUA, is a way that the FDA manages the availability of medical devices, therapeutics and vaccines during public health emergencies. EUA enables the FDA to permit the use of unapproved medical products in an emergency to treat or prevent potentially fatal diseases, as long as certain criteria are met.
Criteria for EUA
According to the FDA, although the COVID-19 vaccines were developed in an unprecedentedly fast manner, they have been rigorously tested and deemed safe as they have successfully passed through each of the following phases:
Phase 1: The vaccine was administered at varying dosages to approximately 20 to 80 people in good health to assess its safety. This phase serves to collect initial data about how well the vaccine induced immune responses in subjects.
Phase 2: The vaccine was tested on a larger sample with hundreds of individuals with varying health statuses and different demographic groups to provide additional information on short-term side effects, risks, efficacy and relationships between dosage and immune response.
Phase 3: “The vaccine is generally administered to thousands of people in randomized, controlled studies involving broad demographic groups” to collect additional safety data, according to the FDA. In this phase, participants may receive a placebo shot instead of the real vaccine.
Busting COVID-19 Vaccine Myths
The COVID-19 vaccine cannot make people infertile.
The question of whether or not the COVID-19 vaccine can impact fertility has flooded online forums and circulated in public discourse — the answer is a resounding no.
"There is no merit to that concern. Absolutely none. I cannot say that enough," Audrey Merriam, an assistant professor of obstetrics, gynecology and reproductive sciences and the lead investigator in Pfizer's COVID-19 vaccine trials for pregnant women at Yale, said.
Merriam assumes that some people might speculate that the vaccine could have this effect because of the genetic implications that they associate with terms such as "mRNA.” But she vehemently stressed that COVID-19 vaccines have no such effect on people's genes.
"There's no chance for it to integrate into your DNA or cause any changes to it or make it mutate or cause your egg cells to have any kind of mutation because of this vaccine," she said.
The COVID-19 vaccine does not affect people’s DNA.
Since the Pfizer and Moderna vaccines are the first mRNA-based shots to have been widely distributed in the United States, Merriam believes that some people might wonder whether they may have genetic impacts.
"Even though this is an mRNA vaccine, your body is responding to it in a similar fashion to any other vaccine, where it recognizes something as foreign, your white blood cells respond and they make antibodies," Merriam explained. "It doesn't go into your DNA."
Merriam emphasized that the mRNA in the COVID-19 vaccine is actually degraded faster by the body than most other vaccines, meaning that it does not get a chance to stay around long enough to have any sort of impact on your DNA.
Photography by Regina Sung, Marisa Peryer, Wikimedia Commons
Credits:
Cover photo by Regina Sung, Contributing Photographer. Design by William McCormack.