Viral Transmissions Glossary

This forms a running glossary for my Viral Transmissions newsletter (previously known as COVID Transmissions), found at viraltransmissions.substack.com

Adaptive immunity

Adaptive immunity represents the immune machinery that recognizes a specific infection — the strep bacteria that gave you a sore throat when you were four years old, for example — and allows your body to provide a response that deals with that infection.

Adjuvant, vaccine

A vaccine adjuvant is a substance added to the vaccine to assist in the generation of an immune response. Adjuvants can be any number of substances that encourage inflammatory immune responses. The CDC has an excellent page on adjuvants here: https://www.cdc.gov/vaccinesafety/concerns/adjuvants.html

Antigen

An antigen is a pathogen-produced substance that stimulates an immune response. It is usually a smaller component of a pathogen’s overall machinery that is accessible to the immune system. Every pathogen produces different antigens, and patient immune systems respond to different pathogens. There are usually trends overall in which antigens generate an immune response, but there is individual variation as well.

Antigenome

A “mirror” copy of the virus genome that the virus creates as a template to make more copies of its own genome. RNA and DNA can be created in two “senses”; only one sense, the “positive” sense, allows for an RNA molecule to be translated into protein. The SARS-CoV-2 genome is positive sense, but you cannot directly copy a positive sense genome from another positive sense genome. Instead, you need to make an intermediate, a “negative” sense strand that serves as a template to create more positive-sense genomes. Think of it as kind of a mold for creating copies of a sculpture. Yes, you could theoretically sculpt a new, exact copy of something, but it would be very hard. If you create a mold, however, which is complementary to the sculpture but uses negative space to describe the sculpture’s shape, you can fill that mold many times to make many copies of the sculpture. In the same way, the virus genome is copied into a “negative” antigenome, which then forms a template for the rapid and efficient creation of virus genome copies.

Asymptomatic

Typically refers to infections that never develop any symptoms at all; the patient never notices they were infected. This can be confusing because while a patient may not have symptoms during the “incubation period,” if they do eventually develop symptoms, their case is not considered asymptomatic. Also see subclinical.

B cell

B cells are the chief producers of antibodies in the body. They are related to T cells but serve a different function. T cells and B cells work together to produce a humoral (ie blood-based) immune response. Also see T cell.

Boost or booster dose

Any dose of a vaccine given after the first, “prime” dose. Also see prime.

Control

Control means that the incidence, prevalence, morbidity, or mortality resulting from an infectious disease have been reduced to a locally acceptable level; an example of this would be diarrheal diseases in the US.

Correlate of protection

Let’s break this one down. “Protection” is something that we determine by epidemiology. We look at a population, and if we see less infection in that population than some comparator population, we call that population “protected” to some degree. But we know that protection is the result of immune responses. This is where we get into “correlates.” This will not surprise anyone who has immunology training, but we are really, really confused about how immunity actually works. Science has discovered some incredibly complex systems available to us that protect us against pathogens; they are so complex that for every pathogen, it requires a large amount of research to figure out which system is actually the one protecting us the most. What we typically do is find evidence of an immune response (eg, antibodies, cells that react specifically to the infection, etc.) that we know is commonly and significantly associated with people in protected populations. In other words, we figure out who is protected and then we figure out what immune responses exist in people who are protected — these immune responses correlate with protection, and accordingly are named “correlates of protection.” These can be hard to figure out — right now we do not know the correlates of protection for COVID-19. However, it’s worth noting that we also don’t know the correlates of protection for pertussis, a disease against which we have a very nice vaccine.

Ct (“cycle threshold”)

Cycle threshold, written as “Ct,” is the output of a quantitative real-time PCR test, not only testing for the presence of RNA, but also counting the amount of that RNA. PCR doubles the amount of a specific sequence present in a sample with every cycle. The “cycle threshold” is the earliest cycle that the RNA of interest becomes detectable. The lower it is, the fewer doublings it takes for the RNA to be detected — this means the lower the Ct, the more RNA there originally was in the sample. For a more in-depth explanation, please see this issue of COVID Transmissions: https://covidtransmissions.substack.com/p/covid-transmissions-for-12-31-2020

Elimination

Elimination means that within a local area, the incidence of an infection has been reduced to zero by deliberate efforts, but continued interventions are still required to prevent reintroduction; an example here might be polio virus infection in the US.

Eradication

Eradication means that globally, through deliberate efforts, the incidence of an infection has dropped to zero and interventions are no longer required to prevent its return; the only universally agreed-upon example of this in human history is smallpox.

Extinction

Extinction means the pathogen no longer exists anywhere — not in animals, not in humans, not in laboratory samples; this has never happened by deliberate action.

Herd immunity

Herd immunity is a somewhat casual term for a population-level indirect immunity by which people are protected from getting sick by being surrounded by others who are immune. Herd immunity is essential to most population-based vaccination strategies, because no vaccine is perfectly effective in all patients, and some patients have underlying medical conditions that make it impossible for them to receive a vaccine. Instead, they rely on being surrounded by a society where most people are vaccinated and immune, so that infectious agents have no way of getting to them — the situation where so many people are immune that the small susceptible population is protected indirectly is called “herd immunity.”

Innate immunity

Innate immunity is a set of generalized responses to infections that cut across broad categories of infections. Innate immune mechanisms may respond to viruses in general, or to bacteria in general, but they are not thought to respond to specific pathogens like the 1918 influenza virus strain or the specific strain of strep that you had when you were four years old.

The innate immune response offers the ability to deal with some minor infections, but it only slows the more serious pathogens down. In those situations, the innate immune response buys time for the adaptive immune response to provide a more specific remedy for infection.

Interferon

Interferons are a class of proteins produced by the body to effect immune responses. Type I interferons are part of the initial response to virus infection and activate an antiviral response that makes the local cellular environment much more hostile to virus infection. Type II interferons are more relevant to communications between cells in the immune system and are also involved in responses to bacterial infection. Type III interferons are less well-understood, but appear to be involved in longer-term, sustaining responses to virus infection.

mRNA

“Messenger” RNA. RNA means “ribonucleic acid,” and is a similar type of molecule to DNA, but a bit less stable. RNA is used for a number of biological tasks, but as mRNA it represents instructions to the cell to make a specific protein. Every protein in the body started out as an mRNA instruction at one point or another. mRNA is easy and quick to artificially synthesize, which is why mRNA vaccines are at the head of the pack in the race to develop a COVID-19 vaccine.

Mucosal immunity

Mucosal immunity refers to the capacity for protection against a given pathogen at a mucosal surface — mucosal surfaces are interfaces between the inside of the body and the outside world, such as the respiratory system’s air-facing surfaces, or the food-facing portions of the digestive system. In other words, places like your mouth, your airways, your gut, etc all have “mucosa,” and mucosal immunity is specialized protection against a specific pathogen developed in one of these tissues. Immune cells can make a contribution to mucosal immunity, but so can specialized mucosal antibodies known as IgA.

Neutralizing antibody

Not every antibody is effective at hindering viruses. There are a lot of reasons for this, but mostly they relate to the fact that viruses replicate themselves very efficiently and saturate the area with their copies. This means that immune responses that involve cells eating every infectious particle are often too slow to be effective. For this reason, people are often interested in antibodies that “neutralize” the virus. Neutralization refers to stopping the targeted pathogen from being able to be infectious or pathogenic; it renders it inert. Antibodies can target any part of the virus, but not all parts of the virus are involved in actually infecting cells, so only antibodies that target key antigens involved in the infection process will be “neutralizing.” There are experimental systems that can be used to assess whether or not antibodies are neutralizing or not. If there is interest (please comment), I can go into more depth on this in a future issue of the newsletter.

Phase 3 trials

The largest-scale, latest-stage clinical trials. In Phase 3, a product is very nearly ready for market, and researchers are focusing on whether or not it works — in a clinical trial, this is called “efficacy.” Safety is still part of the study as well, but at this stage it is expected that most potentially extreme safety events will have been detected in earlier phases of study.

Placebo

In clinical studies, a “placebo” is a fake or “sham” treatment that is meant to stand-in as a comparator for the active treatment being studied. The human brain is very susceptible to suggestion, and has a lot of effects on our overall health. Being given even a sham treatment can have effects, so we use placebos to ensure that whatever active treatment we are giving is doing better things than just a sham intervention might accomplish. Placebos are often a sugar pill or a saline solution, but can take many other forms. Also, not all trials use a placebo — some use an efficacious treatment that is not expected to perform as well as the new treatment being studied. Many vaccine trials use a real vaccine — but against a different disease; this would actually be considered a placebo, but one that has effects on the body that closely mirror the treatment that we’re actually interested in studying, to improve the quality of comparison.

Preclinical

Preclinical studies are those that are done before a treatment goes into humans. They can include early experiments in cell culture and other biochemical models (“in vitro”, from Latin for “in glass,” like a test tube), but animal experiments are also a key part of the preclinical study process (“in vivo,” from the Latin for “in a living thing”).

Prime or prime dose

The first dose of a vaccine series for a specific pathogen or set of pathogens. For example, in the Hepatitis B virus vaccine series, the prime dose is generally given within the first week of life — sometimes immediately after birth. Booster doses — that is, any doses after the first — are given years later, in that vaccine’s case. Prime-boost schedules can vary widely across vaccines. See also booster.

Prognostic biomarker

A prognostic biomarker is a biological measurement that can be made to predict the course of a disease — how well or poorly the patient might do. Contrast this with a predictive biomarker, which tells you how likely the patient is to respond to a particular treatment, or with a diagnostic biomarker, which tells you whether or not the patient has a certain disease. An example is LDL cholesterol, which is used as a prognostic biomarker for cardiovascular disease.

Reactogenicity

The capacity of a vaccine to produce adverse reactions; in other words, how intense the safety events are upon vaccination. This is one of those words where I’m not sure we really needed at technical term, but I don’t make the rules.

Reproduction number

The reproduction number R is the average number of infections that result from a single infection in an outbreak of a contagious disease. This is also called the “effective reproduction number,” which accounts for variables unique to a specific outbreak and thus takes into account disease control measures. This is not to be confused with the basic reproduction number, “R-naught,” which is usually defined as the number of infections that are expected to result from a single infection in an outbreak where no one in the population is immune and where no control measures are taken.

Seroconversion

Seroconversion is a term for when antibodies become notably detectable in blood. Seroconversion is important because it signals when the body has had a sufficient exposure to a given antigen to elicit an immune response. Seroconversion, however, is not an objective term. It is generally defined by a consensus view of what represents a substantial increase in the blood level of antibodies that react to a certain antigen.

Spike glycoprotein (S)

This is the name of a surface protein on SARS-CoV-2. In coronaviruses, the “spike” protein is the protein that is responsible for attachment to cells (literally just sticking to them) as well as the process of entry, which gets the virus contents into the cell where they can start to do their work. The fact that the S protein is involved in these functions, as well as being on the surface of the virus where it is accessible to the immune system, makes it a target of vaccinologists. “Glycoprotein” is just a term meaning that sugar molecules are attached to the S protein as it is being made, which is a common feature among surface proteins. These sugars sometimes affect the way the immune system reacts to the protein.

Sterilizing immunity

Sterilizing immunity is an immune protection level in which infection with a pathogen is completely prevented. The subtlety that is important here is that infection does not always equal disease; you can be infected with a pathogen and not necessarily get sick. In sterilizing immunity, not only do you not get sick, you don’t get infected at all. Sterilizing immunity is extremely rare.

Subclinical

This refers to disease cases that are not severe enough for the patient to report for clinical care. Disease might be so mild that the patient isn’t even sure they are sick.

T cell

T cells are a type of white blood cell that is central to human immune responses. T cells engage in a wide variety of functions, but are important for specific responses generated to the pathogens that each person experiences in life. T cells can help to support antibody responses, prevent the body from attacking its own tissues, or kill infected cells, among other functions.

Virion

A complete, infective particle of the virus.

Zoonotic/Zoonosis

A zoonosis is a disease that passes from animals into humans. A disease is zoonotic if it is a zoonosis. SARS-CoV-2 is thought to have originated as a zoonotic disease-causing pathogen. At this point it is largely human-to-human, however.