Dr. Philip McMillan,  John McMillan

Millions of people who rolled up their sleeves for their third COVID-19 shot never imagined their immune systems might be undergoing a perplexing shift that scientists are only beginning to understand. Deep inside, their bodies were stealthily producing a type of antibody that typically appears in beekeepers and people receiving allergy treatments, not in those fighting off viruses.

This antibody, called IgG4, is now at the center of an emerging scientific mystery that could reshape our understanding of COVID-19 immunity.

Your Body’s Security Detail: Meet the Players

Think of your immune system as a sophisticated security detail. Different antibodies serve as specialized guards, each with unique roles. Most infections activate the “aggressive responders,” IgG1 and IgG3 antibodies that sound the alarm and rally the body’s defenses. These antibodies typically dominate the response to infections, signaling other immune cells to attack invaders.

Then there’s IgG4, the peacekeeper that plays a regulatory role. It acts as what some immunologists call a “tolerant” antibody.

“The immune system will recognize [a beekeeper], OK, he’s being stung all the time. We don’t want to overreact to it. And so therefore, the immune system will then suppress the immune response with IgG4,” explains Dr. Philip McMillan, a clinician and researcher who has studied this phenomenon extensively.

IgG4’s job is essentially to tell other immune cells, “Stand down, this isn’t a threat.” It’s crucial for preventing overreactions to harmless substances or repeated exposures, like those bee stings. But what happens when these peacekeeping antibodies start responding to a virus we actually want to fight vigorously?

A Surprising Discovery

Scientists examining blood samples from people who received multiple mRNA COVID-19 vaccinations noticed something unexpected: their IgG4 antibodies against the spike protein skyrocketed, increasing by a staggering 3,800% after the third dose.

This pattern looks nothing like what happens after natural infection; instead, it seems specifically linked to repeated exposure to the spike protein through mRNA vaccination, though adenoviral vector vaccines also show the effect to a much lesser degree.

By comparison, natural COVID-19 infection produces an antibody profile dominated by IgG1 (approximately 90%) with minimal IgG4 (around 1%).

• Natural infection alone: ~90% IgG1, ~1% IgG4
• Prior infection followed by mRNA vaccination: ~88% IgG1, ~9% IgG4
• mRNA vaccination followed by infection: ~50% IgG1, ~41% IgG4
• mRNA vaccination without infection: ~50% IgG1, ~45% IgG4

“When this first came out, this was huge,” Dr. McMillan notes. “It was like, wow, how can this be explained? And very sadly, I think the scientific community just kind of ignored it.”

What This Might Mean for You

This unusual antibody shift may explain some puzzling patterns we’ve seen:

Why vaccinated people still catch and spread COVID: If nearly half your antibodies are essentially saying “ignore this virus,” it makes sense that the virus might replicate more easily, even if you have high antibody levels overall.

Why vaccinated people typically get milder illness: The same IgG4 antibodies that allow the virus to persist might also prevent the dangerous inflammation that damages lungs and other organs in severe cases.

As Dr. McMillan puts it: “It could be one of the main reasons why we are having high circulation of virus in highly vaccinated regions. Additionally, I would go as far as saying that I think it’s one of the major reasons why we could see reduced severe COVID-19 in vaccinated cohorts as well, simply because of this immune-tolerating effect.”

The Rebound Question

Here’s where things get especially interesting and potentially concerning. What happens when IgG4 levels eventually decline?

Dr. McMillan raises a thought-provoking possibility: Could the body, after being in “tolerate mode” for months or years, suddenly mount a dramatic inflammatory response when that suppression lifts?

Early in the pandemic, doctors recognized COVID-19’s hallmark cytokine storms, extreme inflammatory reactions, because they primarily affected the lungs, causing obvious breathing difficulties. But similar inflammatory processes could theoretically target any organ.

“What happens if it’s a kidney cytokine storm, a heart cytokine storm, a brain cytokine storm, an intestinal cytokine storm?” Dr. McMillan asks. “Suddenly, it gets very difficult to pick up. It’s not so easy to work out.”

Pieces of a Larger Puzzle

This IgG4 phenomenon isn’t proof of harm. It’s a scientific clue that merits further investigation. Many vaccinated individuals have remained perfectly healthy, suggesting that for most people, this immune shift may have limited practical impact.

Still, understanding these nuanced immune responses could help explain why:

• Some people experience repeated COVID infections despite vaccination
• Long COVID affects certain individuals but not others
• Inflammatory symptoms sometimes appear weeks or months after infection

The scientific community needs to investigate key questions:

• How long does this IgG4 shift last?
• Does it affect protection against new variants?
• Are certain people more prone to developing high IgG4 levels?
• Could it influence how we approach future booster shots?

If the main benefit is immune suppression, are there more effective ways to achieve that?

Going Forward

The IgG4 story reminds us that the human immune system is incredibly complex, far more sophisticated than simple “strong” or “weak” responses. As we continue to study COVID-19’s long-term effects, these immunological nuances may help us understand the full spectrum of post-infection and post-vaccination experiences.

For now, researchers like Dr. McMillan are calling for more research into this overlooked aspect of COVID immunity. By following the evidence wherever it leads, even when it reveals unexpected patterns, medical science can better understand the root causes of this devastating pandemic.