Why antibody levels do not equal "immunity": Part 1

The CDC has an unhealthy obsession

We constantly hear about how great antibodies are. We now have COVID-19 “boosters” that are supposed to combat “waning efficacy” of the COVID-19 vaccines by raising the levels of antibodies against SARS-CoV-2.

These antibodies are supposed to bind to the spike protein on the surface of the SARS-CoV-2 virus. Since spike protein is thought to help the virus get into our cells, the idea behind vaccination is that some of the anti-spike antibodies will bind to spike and help “neutralize” the virus.

Image from here, showing a SARS-CoV-2 virion and a close-up of a spike protein and its different parts.

Sounds great right? In fact, can we say that immunity to a virus is marked by the presence of antibodies against that virus?

That’s what the CDC seems to suggest. Here’s what they say about immunity:

Immunity to a disease is achieved through the presence of antibodies to that disease in a person’s system.

On their page about “immunity types,” they mention “antibody” or “antibodies” eight times:

Screenshot from here, discussing the “types of immunity,” according to the CDC.

This is a horribly misleading way to define immunity.

How should we define “immunity”?

Before we talk about why the CDC’s definition of immunity is misleading, let’s try to define “immunity.” It’s actually not straightforward to define.

The textbook Kuby Immunology defines immunity as “a state of protection from infectious disease.” Janeway’s Immunobiology textbook defines it as “the ability to resist infection.”

From Kuby Immunology

That begs the question: what does it mean to be able to “resist” an infection, or be “protected” from an infectious disease?

Well, most people would probably agree that if someone exposed to a respiratory virus was able to fight it off with no symptoms, then that person was “immune.”¹

Perhaps we’d also say the same about someone who only exhibited some mild symptoms for a short period of time. But what about someone who got the virus and was bed ridden for over a week, but survived? Can we say that person was also immune since they did eventually “resist” the virus?

What most people would probably agree on is that someone who got the virus and got so sick to the point of death, only surviving because of some extreme medical intervention, was not “immune.”

I won’t attempt to precisely define “immunity” here. But let’s just say that if a person is able to fight off a SARS-CoV-2 infection without interventions typically encountered in a hospital, like intravenous injections or intubation, they at least exhibited some level of immunity. I recognize that this is somewhat arbitrary and still a bit vague, but we have to start somewhere.

How necessary are antibodies for fighting off SARS-CoV-2?

Now let’s get back to what’s wrong with the CDC’s definition of “immunity.”

Let’s start with how it’s possible for people to fight off SARS-CoV-2 infection without specific anti-SARS-CoV-2 antibodies in their blood. In fact, you may have done this yourself, or know people who did.

Unvaccinated people with no prior SARS-CoV-2 exposure

Unvaccinated people who had no exposure to SARS-CoV-2 before, and therefore didn’t have “SARS-CoV-2 specific antibodies,” routinely survive SARS-CoV-2 infection. This includes the many people who got SARS-CoV-2 before the vaccination rollout, as well as people who remain, to this day, unvaccinated.

Now, we can’t necessarily say that these people survive with no help at all from serum (blood) antibodies. That’s because, according to this study (Fig. 2), SARS-CoV-2-specific antibodies become measurable in the blood after a few days from symptom onset, although it takes longer for them to reach peak levels.² Some of these antibodies might indeed be helpful for fighting off infection.³

From Fig. 2 here.

People who don’t respond by making antibodies

But let’s look at this study: Lack of antibodies to SARS-CoV-2 in a large cohort of previously infected persons

In our population with previous RT-PCR confirmed infection, approximately one in 16 persons lacked IgG antibodies.

“IgG antibodies” are a class of antibody. They found that 1 in 16 people (6.25%) did not have detectable levels of anti-SARS-CoV-2 IgG antibodies.

They also found that “absence of antibodies varied independently by illness severity, race/ethnicity, obesity, and immunosuppressive drug therapy.” That’s curious.

Is it possible that these people were not actually infected and those were false positive PCR test results?

But other studies have found similar things. This study found about 17% of people had undetectable anti-SARS-CoV-2 IgG antibodies: Cellular Immunity in COVID-19 Convalescents with PCR-Confirmed Infection but with Undetectable SARS-CoV-2–Specific IgG⁴

This study reported that 30% of recovered patients generated either very low or undetectable levels of neutralizing antibodies: SARS-CoV-2 specific antibody and neutralization assays reveal the wide range of the humoral immune response to virus

About 30% of 248 recovered patients generated a very low level of NAb titers… and NAb titers in ten of them were below the limit of detection…

Patients who did not generate NAbs at the time of discharge did not develop NAbs thereafter.

“Nabs” stand for neutralizing antibodies.

In response to this, the authors said:

How these patients recovered without the help of NAbs and whether they were at risk of re-infection of SARS-CoV-2 should be further explored.

It should indeed be further explored.

People with genetic disorders that prevent antibody production

Now consider the case of people with X-linked agammaglobulinemia (XLA), which is a genetic disorder characterized by an inability to produce B cells (which make antibodies), or the antibodies that B cells make.

It’s possible for these people to survive SARS-CoV-2 infection without extreme medical interventions: X-Linked Agammaglobulinemia and COVID-19: Two Case Reports and Review of Literature

The role of B cells in evading SARS-CoV-2 is not completely understood. In the case of patients affected with XLA, the absence of B cells does not increase the severity of the disease. In fact, it may be protective but may lead to delayed recovery.

The reason they say XLA could be “protective” is that people with XLA wouldn’t be able to make certain inflammatory cytokines that come from B cells. This might actually prevent the hyperinflammation commonly associated with severe cases of COVID-19.

It’s not that having XLA is great for fighting off SARS-CoV-2; people with XLA seem to take longer to fight off the virus, and there are certainly reports of XLA patients who were hospitalized from SARS-CoV-2 infection.

But the point is that people like this can survive.

People on B cell depleting meds

Lastly, consider this case report: COVID-19 in a MS patient treated with ocrelizumab: does immunosuppression have a protective role?

That was about a 58-year old man who was on ocrelizumab, a drug for multiple sclerosis (MS). That drug depletes B cells, which are the cells that produce antibodies. The man got COVID-19 with “persistent high fever and severe cough,” but survived. He had “complete B-cell depletion” at the time. The only thing he was given was paracetamol (acetaminophen, aka Tylenol) to treat his fever.

There are other case reports like this.

Here’s one about a 42-year-old man and 39-year-old woman who got COVID-19 while on ocrelizumab: Negative SARS-CoV-2 antibody testing following COVID-19 infection in Two MS patients treated with ocrelizumab

The man’s initial symptoms of COVID-19 included “fever, cough, and impaired taste.” This progressed over several days to involve labored breathing on exertion. However, he did not require hospitalization. His respiratory symptoms resolved after two weeks, though the impaired taste persisted for over a month.

The woman had a mild course and her respiratory symptoms lasted only two days.

Here’s another example: Favorable outcome after COVID-19 infection in a multiple sclerosis patient initiated on ocrelizumab during the pandemic

That reports of a 39-year-old woman who was on ocrelizumab. She “developed a low-grade fever and mild dyspnea” (labored breathing) in response to COVID-19. She recovered relatively quickly. Interestingly, her husband got COVID-19 at around the same time, so they probably got the same SARS-CoV-2 strain, but he required hospitalization. He did not have MS and was not on the drug.

Finally, this study characterized 51 people on ocrelizumab: COVID-19 in ocrelizumab-treated people with multiple sclerosis

They found that COVID-19 severity was in line with that of the general population. Most patients did not require hospitalization, and “there was no association between duration of exposure to ocrelizumab and COVID-19.”

[UPDATE 1/21/23: It should be noted that this paper reported that some of the patients did have some serum antibodies. Unfortunately we don’t have COVID-19 outcomes as a function of antibody level, which would have been the more useful metric than just “duration of exposure to ocrelizumab.” So take these results with a grain of salt.]

The primacy of antibodies?

These results don’t mean that antibodies can’t be helpful for fighting off SARS-CoV-2 infection. But it casts doubt on the primacy of antibodies.

At the very least, it means that there are other components of the immune system that are involved in fighting off SARS-CoV-2. In fact, some researchers have proposed that neutralizing antibodies are secondary to those other components.

In Part 2, we’ll dig into why they say that. Stay tuned.

1. In textbooks you’ll usually see “immunity” split up between “innate” and “adaptive” immunity. Adaptive immunity, which includes T and B cells (which make antibodies), is responsible for responding to specific antigens and is thought of as the component of our immune system that has a “memory” of past infections. Some people only think of “immunity” as having been conferred if adaptive immunity has been activated (like antibodies were produced). However, this is arbitrary, and even if we were to agree that “immunity” needs to have some kind of specific “memory” component to it, arguably we should still include activation of the innate immune system, because it also has “memory” components to it. This is sometimes called “trained immunity.” More here.

2. Some studies report serum antibodies as first becoming detectable later than what this study reports, but that might be because this study was using a more sensitive detection method.

3. Some people may have also started out with antibodies against related coronaviruses that they’d been exposed to in the past (see here).

4. This was 60 days after symptom onset.