Immunity Debt: A Catalyst for the Development of Infections and Autoimmune Disease?

IF THE COVID-19 pandemic taught us anything, it is to expect the unexpected. Unfortunately, that unexpected could be happening now with increasing risks of severe infections thanks to an unintended consequence of social distancing, hypervigilant cleaning and fewer doctor visits and vaccinations. It seems these important measures put in place by necessity to help stem the spread of the SARS-CoV-2 virus may also have had the unintended consequence of causing a backlash of infections — a concern known as “immunity debt.” Natural, or innate, immunity is a frontline defense against invasive pathogens, prompting the immune system to develop an adaptive response. With more exposure to pathogens and viral loads, innate immunity theoretically increases in effectiveness, spurring immune stimulation. Much like early exposure to peanuts may ward off the development of a peanut allergy, early exposure to pathogens and viral loads can lead to a robust immune system.

But during the COVID-19 lockdowns, hospitals saw unprecedented reductions in routine care visits, as well as nonemergency community-acquired viral and bacterial infections such as viral gastroenteritis, chicken pox, upper and lower respiratory tract infections, Streptococcus pneumonia and Haemophilus influenza b. Despite this, infections initially remained lower post-lockdown than during prepandemic levels. And, while that sounds positive, mathematical models suggest the loss of herd immunity for these and other diseases has the potential to cause more intense and widespread infections — possibly for years to come.¹

Immunity Debt on a Worldwide Scale

As the world began to reopen after two-plus years of minimal exposure to microbes, scientists in some parts of the world saw a rebound in infection rates for conditions such as respiratory syncytial virus (RSV) and influenza, as well as atopic inflammatory diseases. Particularly at risk for these infections were children, the elderly and the immunocompromised.

Now, the implications of immunity debt on world health are becoming reality, particularly for some early childhood infections. For example, New Zealand saw very low levels of RSV (usually a significant cause of hospitalizations) while under lockdown, but a rapid increase in the number of cases after a partial border reopening in April 2021 — five times higher, in fact, than the 2015 through 2019 peak average.² Australia also saw a virtual absence of both RSV and influenza during the pandemic, but even larger outbreaks than usual by October 2020.¹ In the U.S., RSV cases spiked in the summer of 2021, particularly in southern states, even though infection rates are usually higher in the winter.

Without the natural protection that exposure to RSV provides, and without a vaccine to protect against it, immunity debt and rebounding post-epidemic infections may make future epidemics even more severe.

Hygiene Hypothesis and the Rise of Autoimmune Disease

Extrapolating this hygiene hypothesis to the use of protective measures put in place during the pandemic, questions remain as to whether reduced and delayed infections may have a larger eventual impact on the incidence of autoimmune and allergic disease.

As rates of bacterial infections decrease, a coincidental increase is often seen in autoimmune and allergic diseases, a phenomenon often found in developed countries where use of antibiotics and antimicrobials is high. This is explained by the hygiene hypothesis, which proposes an overzealous use of antibiotics and antimicrobials and subsequent limited exposure to pathogens lead to a compromised immune system, suggesting an imbalance of microbiota, particularly in the gut, may be affecting immunoregulation.

Currently, antinuclear antibody biomarkers for autoimmune diseases are on the rise in the U.S., particularly in males, non-Hispanic whites, adults 50 years and older and adolescents. And, since this phenomenon cannot be explained by genetics, investigators are considering environmental factors³ since, as populations move from one place to the next, they tend to be affected by immune diseases at the same incidence as their adopted homeland.⁴

There is also a rise in immunocompromised states, which could be caused by cleanliness. When the environment is too clean, the immune system doesn’t have the opportunity to fully develop, causing its defenses to become inadequate. Remarkably, exposure to germs is beneficial. Early childhood exposure to germs helps the immune system to develop and recognize the good from the bad. Even in utero, a mother’s exposure to germs can help to strengthen the fetus’ immune system and gut microbiome.

An increase in autoimmunity can be further explained by the use of antibiotics, particularly in childhood, which may prevent colonization of beneficial microbiota and cause the immune system to attack harmless bacteria.

There are numerous examples that strengthen the case for the hygiene hypothesis. Chronic allergic diseases and asthma are more likely to occur when early exposure to immune-stimulating endotoxins that trigger the molecular “switch” TLR4 are low. It is also thought that a weakened immune system could be a contributing factor for the development of asthma in infants exposed to viral RSV pathogens. In more robust immune systems, RSV will trigger the same TLR4 “switch”; however, for reasons still unclear, when the immune system is lacking, exposure to RSV may instead trigger asthma rather than protect against infection.⁵

Asthma and allergies are being studied through the lens of the hygiene hypothesis relating to hepatitis A. The long form of the TIM-1 gene acts as a receptor for hepatitis A on the immune system. It is also critical to the development of asthma and allergies. The rates of hepatitis A have fallen dramatically since the 1950s, but since then, the rates of asthma and allergies have been on the increase. Perhaps not coincidentally, since that time, sanitation has also improved. The longer version of TIM-1 seems to act as a protector against asthma and allergies, but particularly so in those who have been infected with hepatitis A. It is theorized that the binding of hepatitis A to immune cells and efficacy of the killing of T cells may be enhanced by the long form of TIM-1, ultimately providing protection against asthma and allergies.⁶

Microflora Hypothesis

More recently, the microflora hypothesis links early exposure to a variety of environmental influences on immune system development. The more robust the intestinal microbiota, the more robust the microbiome development, and less propensity toward inflammatory states, including food allergies and allergic diseases. For example, infants with less gut microbial diversity between 3 months to 1 year of age, measured by enterobacteriaceae/bacteroidaceae ratios, have an increased rate of food sensitivity, suggesting the first year of development is crucial to precluding immune hypersensitivities later in life.⁷ Of course, a host of factors are at play when it comes to influencing whether one is susceptible to allergies, including genetics. It is too early to know with certainty what role, if any, microflora play, although it appears a promising area of research.

Immunity Debt or Vaccination Crisis?

In addition to a decline in natural immunity, a decrease in vaccination coverage is a real concern. Prior to the pandemic, vaccination rates were relatively high, particularly in developed countries, thanks to mandatory childhood vaccinations and generally good adherence to vaccine recommendations in other age groups. However, during the pandemic, a reduction in doctor visits, including well-baby visits, resulted in reduced vaccination rates, in some cases sharply. “Availability of the vaccine was not a problem during the pandemic, but access was,” says Teale Ryan, MSN, RN, a PhD student at the University of Kansas Medical Center. “Just like routine preventive care was missed during the first year of the pandemic, so were routine vaccines. People in lockdown, especially in larger cities, didn’t want to leave their homes. Healthcare providers were also doing large amounts of their work through telehealth.” These factors have not yet returned to normal.

As such, some people question whether the greater challenge is immunity debit or a vaccination crisis. According to Ryan, there is a lot of COVID-19 vaccine misinformation, including that the vaccines don’t prevent the disease, causing vaccine hesitancy. But, of course, research shows that the vaccines greatly reduce the chances individuals will become infected with the SARS-CoV-2 virus if they are vaccinated. And, they are greatly protected against severe disease. In fact, according to Stanford researchers, vaccinated persons had better immunity against future COVID-19 strains than those whose only immunity was a previous infection. In their study, vaccinated participants who became infected with alpha or delta variants began to generate antibody panels that recognized and bound to the viral spike protein (in this case, the Wuhan-Hu-1 virus), as well as the viral spike protein of other variants. On the other hand, antibodies produced in unvaccinated individuals would bind to the viral spike protein of only the alpha or delta variants. In addition, the antibodies produced solely through past infection showed bias toward the strain of the original infection and a lowered ability to bind to the spike proteins of other variants. The researchers speculated that the reason for this could be germinal centers in the lymph nodes that actively amplify antibodies for weeks after a vaccination. In contrast, antibodies generated by the unvaccinated but previously infected were variable and dropped steadily once the infection passed.⁸

The World Ahead

Although the risks of immunity debt are real, from a practical standpoint, the usual and universal precautions may be all that is necessary to lead a life well-lived in as safe an environment as possible. Enabling the best immune response through vaccinations, drug treatments and lifestyle choices is the best course of protection against current and future infections.