Immunity — a Complex Team Sport

As new SARS-CoV-2 variants emerge, our vaccines continue to protect against severe disease but most people have gotten sick during the Omicron wave. Now, most Americans already have immunity either through prior infection, vaccination, or both (“hybrid” immunity). Why do we still get sick despite being boosted? Why have some people never gotten Covid? And is accepting that Covid is here to stay simply giving up?

We now know more about the layers of immunity to SARS-CoV-2 through infection and vaccination than any other infectious disease. We now know that hybrid immunity offers broad protection against variants, and even another species of virus (SARS1). Getting sick is no fun, but it is your body’s way of preparing to avoid getting sick in the future, even if the virus looks a bit different next time.

Immunity

To be precise, immunity means protection against infection with the virus SARS-CoV-2, which can lead to disease (i.e., COVID-19). Early in the vaccination roll-out, protection against COVID-19 symptoms was very high when the vaccine matched the circulating virus. When the spike protein shapeshifted with Omicron, protection against illness eroded, and the virus was able to make more inroads, sometimes reaching the lungs to cause more serious illness. However, vaccinated people were still less likely to be hospitalized.

Infection vs. Disease

You may be wondering, if vaccines can prevent disease, is there a way fend off infection in the first place? Yes, this is possible. Not everyone who has an infection eventually feels sick. Often, your body’s defenders handle the invasion without you even knowing. This is called an asymptomatic infection.

Infection happens when the spike protein binds to the cells in our upper airways—the mucus membranes lining the nose, mouth and throat which come in contact with everything we eat, drink, and breathe. If the virus manages to enter our cells, it can replicate and make more virus which then infect other cells. Our body responds to this infection by activating an immune response—this is what makes you feel sick (i.e., develop disease).

Innate immunity—generalist first-responders

Let’s assume you go on to feel sick and develop a fever. This is nature’s way of destroying pathogens and sending signals to other immune cells that an attack is underway. These first-responders are generalist defenders. They do not necessarily need to know whether it is a virus, bacterium or fungus—they just know it doesn’t belong. Infected cells are asked to self-destruct, then macrophages carry away the cellular debris to your lymph nodes (e.g., your tonsils and the axillary nodes under your arm).

Adaptive immunity—specialized team players

Within 2-4 weeks of infection, whether or not you ever felt sick, your body will make specific antibodies that attach to the virus. The first antibody to form is called immunoglobulin M or “IgM,” followed by other longer-lasting antibodies called “IgG” and “IgA.” One unique kind of IgA lines the mucus membranes in your nose and mouth: secretory immunoglobulin A (SIgA). This SIgA develops only after recovering from an infection. This is why a nasal vaccine would be very helpful to prevent infection at the point of entry—your nose and mouth.

In addition to antibodies, memory B cells and T cells become activated. The memory B cells remember the invader and can produce antibodies at a later encounter. The two types of T cells (“helper” CD4 and “natural killer” CD8) continue their patrols throughout your body, looking for things that do not belong. When you have another infection, Helper T cells present the B cells with a piece of the invader, called an antigen (such as the spike protein). The B cells then crank out the right type of antibody specific to that antigen. The Natural Killer T cells tell infected or cancerous cells to self-destruct.

An important concept to remember is that antibodies naturally wane over time. Our blood would be too murky with protein build-up if they didn’t. The CD4 and CD8 T cells stay relatively stable, though.

Immunity: vaccination vs infection

Vaccination trains the body against the spike protein, while infection induces specific antibodies against the entire SARS-CoV-2 virus, including the nucleocapsid (N) protein. (Having antibodies to the N protein means you have been infected before.) There are at least two reasons that infection produces good immunity against serious illness. First, the body “sees” more than just the spike protein, which keeps changing. Second, infection induces mucosal immunity by lining the airways with antibodies. Although immunity acquired through infection is very effective (here, here), it can be risky. This is why vaccination is critical, particularly in higher-risk individuals, to reduce the risks associated with inevitable infection.

Germinal centers: the immune system hive mind

After infection, macrophages come through and clean up the debris by depositing dead cells in your lymph nodes, which are drained to your gut through hydration and exercise. During the recovery period, your immune system keeps working to prepare for the next invasion. Special areas of the immune system called germinal centers create slightly different antibodies with mutations and test them to find the best “fit.” This experimentation among antibody-forming cells takes about 6 months, but it’s why people who have breakthrough infection after vaccination develop protection against many different variants. It’s also why a longer interval between vaccine doses induces a stronger boost in antibodies.

Cross-training for good defense

The immune system is a complex matrix of capable first-responders, highly specific threat neutralizers, and a hive mind of engineers refining the antibodies. For those who have been vaccinated and boosted, you have prepared for an eventual infection. When breakthrough happens, it is not your fault nor your body’s failure to respond. It should be expected because vaccination alone cannot provide mucosal immunity, the “Holy Grail” of defense against a respiratory virus. Instead, think of infection as the final phase of immunity-building, not vaccine failure.

The smart defensive strategy at this point of the pandemic is to vaccinate high risk people who are not yet immune, boost those with a weakened immune system, and acknowledge our innate defenses after infection. High-risk patients can benefit from an additional booster, access to rapid testing, monoclonal antibodies and therapeutics in the event of infection. Those who have already been infected with SARS-CoV-2 can boost their protection with a dose of vaccine at least 3-6 months later depending on their individual risks. In all cases, being informed, asking questions, and seeking the advice of a trusted clinician is head’s-up defense in this messy world.