Is Natural Immunity Better Than Vaccination Immunity Against COVID?

There are two ways to become immune to COVID-19: either from previous infection (natural immunity) or from vaccination. But is one better than the other? Many people believe that anything “natural” is better than “artificial” and consequently some pundits, influencers, and bloggers advocate for for natural immunity over vaccination immunity. The COVID Nationwide Antibody Surveillance Survey reported that by February 2022, 58% of Americans had been infected with COVID-19 and thus have some degree of natural immunity. The most recent CDC vaccination data shows that 80% of Americans have received at least 1 dose of a COVID vaccine and 68% have received 2 doses with resultant vaccination immunity. Therefore, most Americans have some degree of immunity one way or the other. Employers and governments are now grappling with whether to mandate vaccination or proof of previous infection as workers return to in-person workplaces.

 

Immunology 101

At the risk of oversimplification, there are two main components of our immune systems – cellular and humoral. Cellular immunity involves T-lymphocyte cells that help fight infection. Humoral immunity involves immunoglobulins (antibodies) that help fight and prevent infection; immunoglobulins are produced by B-lymphocytes. There are five types of immunoglobulins but the three types that are most important for preventing viral infection are IgG, IgM, and IgA. All three of these types of antibodies can be found in the bloodstream but mostly IgA is found on the surface of respiratory cells, such as in the mucus that lines the airways and nasal passages.

When a person gets infected with a virus, the virus uses special molecules on its surface that can bind to cells and then slip inside those cells. These surface molecules are like keys that open the cells allowing the virus to get in. Once inside of a cell, the virus takes over the cell and causes the cell to start to manufacture thousands of copies of the virus (its like what happened to people in the movie Alien). The cell then dies and releases all of the newly manufactured viruses that can then infect more cells.

Once infected with a virus, the body’s immunologic response is to create antibodies to pieces of the virus. Antibodies first start to be produced by B-lymphocytes 5-7 days after an infection with the first antibodies being IgM. Within days to weeks, some of the B-lymphocytes switch to making IgG plus IgM antibodies and the levels of IgM antibodies quickly fall. Over time, the quantity of IgG antibodies in the bloodstream also gradually falls but when the body is re-infected with the same virus, memory B-lymphocytes that had previously been “taught” to make specific antibodies against that virus can ramp up production very quickly resulting in high IgG levels in 1-2 days.

Antibodies fight viral infections in three ways. First, they bind to molecules on the surface of viruses that attach to cells. This is like covering up the “key” so that the virus cannot attach to and get inside of cells. Second, when antibody-coated viruses do get inside of a cell, that cell uses the antibodies as a signal to the rest of the immune system that it is infected, causing other immune cells to attack and kill the cell before it can produce new viruses. Third, when viruses are coated with antibodies, immune cells called macrophages recognize them and “eat” the viruses. The macrophages then digest the viruses and destroy them.

Respiratory viruses, like COVID-19, are first inhaled into the nose and respiratory tract where they get stuck in the mucus that lines those passages. The viruses then infect airway cells and eventually get into the bloodstream where they are carried throughout the body and can infect cells in the heart, liver, brain, muscles, etc. IgA in the mucus of the airways (mucosal immunity) is the first line of defense when a person inhales COVID-19 viruses. IgG in the bloodstream (systemic immunity) is the next line of defense once the COVID-19 virus gets past the airway cells and invades the body.

Antibodies do not always prevent viruses from getting into the body, they just prevent viruses from getting out of control. Since the memory B-cells take 1-2 days to ramp up antibody production, the virus will have a 1-2 day head start to begin to infect cells and reproduce. However, in those first 1-2 days of infection, there are not too many viruses in the body and so a person usually has no symptoms early on (this is the incubation period). Thus neither natural nor vaccination immunity necessarily prevents viruses from getting into the body, they primarily prevent the infection from becoming severe and hopefully prevent you from dying of the infection. In this sense, a viral infection is similar to a mouse infestation in your house – mouse traps in your kitchen can stop the mice from reproducing and eating all of the food in your house but they won’t prevent the mice from getting into the house in the first place.

Because antibodies do not usually prevent viruses from getting into the body and starting to initially reproduce, people with either natural or vaccination immunity can still be contagious to others in those first few days after a virus gets into their body, even though they have no symptoms. The good news is that the number of viruses in the air that they exhale is low and the lower the number of viruses in the air, the less likely it is that someone else breathing that air will become infected.

When a person is infected with COVID, B-lymphocytes in the airways are stimulated to produce anti-COVID IgA antibodies that is released into the airway mucus. Once the COVID virus gets into the bloodstream, blood B-lymphocytes are stimulated to make anti-COVID IgA, IgM and IgG antibodies that are released into the blood. These antibodies recognize different molecules on the surface of the virus and because there are lots of different surface molecules, there are lots of different types of IgA, IgM, and IgG antibodies produced. In other words, COVID-19 infection results in many different types of IgG antibodies. This is different than vaccination immunity.

When a person is vaccinated against COVID, the vaccine is injected into the muscles and then the vaccine gets into the bloodstream. As a result, most of the B-lymphocytes that get stimulated are bloodstream lymphocytes and not airway lymphocytes. These are the lymphocytes are mainly responsible for producing IgM and IgG. B-lymphocytes in the blood also produce some IgA that stays in the blood but since the airway B-lymphocytes are not stimulated, very little airway mucus IgA gets made. Vaccination immunity to COVID also differs from natural immunity because of the types of IgG that are produced. The original Anti-COVID vaccines only produce antibodies against one part of the “spike protein” which is a the molecule on the surface of the virus that the virus uses to attach to cells. If the virus mutates and the spike protein molecule changes shape (as happened with the Omicron variant), then the antibodies produced from vaccination immunity may not recognize this new shape and may be less effective. The new booster COVID vaccines are bivalent and produce antibodies against a part of the spike protein on the original COVID virus and also against a part of the spike protein on the newer Omicron variant.

Natural COVID immunity

Natural immunity to COVID refers to immunity caused by previous infection by COVID. Some people (for example, quarterback Aaron Rodgers) falsely claim “natural immunity” from homeopathic treatments but this is NOT natural immunity. The only ways to develop immunity to COVID is to either have previously been infected by COVID or be vaccinated against it. Because of the different ways that natural immunity and vaccination immunity affect the body’s immune system, both forms of immunity have advantages and disadvantages.

Advantages of natural immunity:

1. Bloodstream IgG production. Human B-lymphocytes have been making IgG in response to infection by various viruses for hundreds of thousands of years and our B-lymphocytes have gotten very good at it.
2. More types of IgG antibodies. Because infection with COVID results in many different types of antibodies against many different parts of the surface molecules of the virus, there is a better chance that some of those antibodies will still work against the virus if a new variant arises with a different shape to just one of the surface molecules. A January 2022 study in the MMWR found that prior to the emergence of the Delta variant, people who were vaccinated were less likely to become infected than people who had previously had a COVID infection but after Delta emerged, those with a previous COVID infection were better protected against future infection than those who were vaccinated. Similarly, a study published two months ago found that previously vaccinated people were 13-times more likely to have a breakthrough infection with the Delta variant than previously infected but unvaccinated people.
3. More mucosal IgA antibodies. Because the COVID virus first stimulates airway B-lymphocytes, those lymphocytes can “learn” to make anti-COVID IgA that gets into the mucus of the nose and airways. Since mucus IgA is the first line of defense, if a person gets re-infected with COVID at a later time, that mucosal IgA can kill off the viruses before they can get into the bloodstream.

Disadvantages of natural immunity:

1. Lower levels of IgG antibodies. Our immune systems are like muscles, they work best when they continue to train. The more you repstimulate the humoral immune system, the stronger it gets. A COVID-19 infection results in a one-time stimulation to the immune system and this can result in lower antibody levels than in a person whose immune system is stimulated by 2 doses of a vaccine followed by booster doses. Some people produce little or no antibodies after infection. A study from September 2021 found that only 64% of people with severe COVID infections causing ARDS had detectable IgG or IgA antibodies after they recovered from infection.
2. You only get natural immunity if you survive the infection. More than 1 million Americans have died of COVID infection. These people’s immune systems never got a chance to make antibodies for long-term protection. Even for those who survived the initial infection, the results of the infection are usually feeling really, really bad for a few days and often having long-term loss of taste and smell. Furthermore, long-COVID symptoms occur in one out of every five people infected. Thus, the cost of natural infection is very high.

Vaccination immunity

Because of the different way that COVID infection and COVID vaccination affect the immune system, there are different advantages and disadvantages with vaccination immunity.

Advantages of vaccination immunity:

1. Bloodstream IgG production. All vaccines work by teaching the body’s immune system to make antibodies and the COVID vaccines are no different.
2. High levels of IgG antibodies. The initial vaccination consists of 2 dose of the vaccine, given 3 weeks apart. This results in the humoral immune system being stimulated twice, as opposed to actual infection with COVID which only stimulates the immune system once. Getting booster vaccinations results in a third, fourth, and fifth time that the immune system gets stimulated. This “trains” the immune system to get very good at producing anti-COVID antibodies. A study from July 2022 found that antibody levels after mRNA vaccine administration were higher and lasted longer than antibody levels after COVID infection.
3. Better protection if variants do not occur. A study from August 2021 found that prior to the emergence of the Delta variant, people who had been infected with COVID but not vaccinated (natural immunity) were 2.3-times more likely to become reinfected than people who were vaccinated but never previously infected (vaccination immunity).
4. You don’t have to get sick to become immune. Although it is true that COVID vaccines can cause side effects, scientific studies as well as my own personal experience show that the side effects of vaccination are way, way, way less than the symptoms of a COVID infection. I have now had 5 different COVID vaccinations and I would take the side effects of all of them combined over even a mild case of COVID infection any day.
5. The vaccines won’t kill you. The vaccines are safe. A study of 11 million people vaccinated with the Pfizer or Moderna vaccines found that there was no increased risk of mortality by getting vaccinated. On the other hand, about one out of every 100 people who get a COVID infection die from the infection. Even those people who survive the initial COVID infection are 233% more likely to die in the year after infection than people who do not get infected based on a study published last December. To put the mortality numbers in perspective, you are 3 million times more likely to die from a COVID infection than to have a winning Powerball ticket.
6. Vaccination after a COVID infection improves immunity. A study from July 2022 found that the effectiveness of infection was 46%, the effectiveness of three doses of a vaccine was 52% but the effectiveness of infection plus three doses of a vaccine was 77%. This is sometimes called “hybrid immunity”.

Disadvantages of vaccination immunity:

1. Single type of IgG antibody. Since the original vaccines resulted in IgG against a specific part of the COVID spike protein, if there is a change in that protein, then the antibodies may not work as well. This was a particular problem with the Omicron variant that caused infection in many people who had been vaccinated earlier. However, even though the vaccines do not work as well if the virus mutates, they do still work and as a result, vaccinated people who get a COVID infection will have milder cases of the infection than unvaccinated people. The newer booster vaccines are bivalent and result in production of two types of antibodies which improves the effectiveness against variants.
2. Lower mucosal IgA levels. Because the airway B-lymphocytes are not strongly stimulated by vaccination, there is lower anti-COVID IgA in the mucus of vaccinated persons compared to those who have previously had a COVID infection. Thus vaccinated persons may not have as strong of a first-line defense against infection. A study from 2021 found that vaccination causes high levels of IgA and IgG in the bloodstream but little to no IgA in the saliva. A study from July 2022 found that infection with the Omicron variant of COVID resulted in 10-times more IgA in respiratory secretions (bronchoalveolar lavage fluid) than vaccination. A second study from October 2022 also found that people previously infected with COVID had higher mucosal IgA levels than vaccinated but not previously infected people.

What does all of this mean?

So, is natural immunity better than vaccination immunity? Well, it depends… We can draw several conclusions from all of the above findings:

• If variants do not emerge, vaccination immunity is better than natural immunity.
• The more boosters a person gets, the better their protection.
• If variants emerge, natural immunity may be stronger than vaccination immunity until new vaccines are developed against those variants.
• Natural immunity plus vaccination immunity (hybrid immunity) gives the strongest protection.
• Although early studies are promising, it is too early to tell if the new boosters that cover Omicron will be better than natural immunity.

For employers trying to decide about whether to mandate vaccination for employees, it is hard to defend a position that vaccination is superior to natural immunity in every case. For example, a person who received 2 shots of the original mRNA vaccines in 2021 may have less immunity than a person who survived an Omicron infection in 2022. Instead of vaccination mandates, a better approach would be immunity mandates by having employees either provide documentation of vaccination or documentation of past infection. However, Americans as a society dislike mandates of any kind and so rather than mandates, it may be better to link immunity documentation to health insurance premium prices, life insurance premium prices, or other employment fringe benefits.

My recommendation is that everyone should get vaccinated and then get as many boosters as you can, including the newest booster that covers Omicron. In theory, immunity from these new boosters should be better than having natural immunity alone. If you have previously had a COVID infection (and are still alive), then get vaccinated and also get the new booster… you can relax with the knowledge that you will then probably have the best immunity against COVID on the planet. We have come to a point in the pandemic where having no immunity (neither natural nor vaccination immunity) is socially irresponsible and only prolongs the pandemic for the rest of us.

October 20, 2022