One of the concerning observations from the COVID pandemic is that immunity from infection (“natural” immunity) appears to be better than immunity from vaccination. This is often attributed to the fact that when a person is infected with COVID, their adaptive immune system creates antibodies against many different parts of the COVID virus whereas an mRNA vaccine produces antibodies only against one specific site on the exterior of the virus. However, the reason for this difference in immunity may be due to something altogether different – infection results in the immune system producing lots of anti-COVID IgA but mRNA vaccines produce relatively little anti-COVID IgA. To understand why this is important, let’s take a look at the function of the different classes of antibodies (also known as immunoglobulins), including IgA
- Current intramuscular COVID vaccines provide good protection against severe COVID infection but offer less protection against mild COVID infection
- Secretory IgA antibodies in respiratory mucus is the main antibody that prevents inhaled viruses from getting into our bodies
- Intramuscular COVID mRNA vaccines create a lot of IgG antibodies in the blood but create relatively little secretory IgA antibodies in respiratory mucus
- Inhaled COVID vaccines offer the potential to create larger amounts of secretory IgA in respiratory mucus and thus provide greater immunity against COVID infection
The basics of immunoglobulins
There are five types of immunoglobulins: IgG, IgM, IgA, IgE, and IgD. Each of them plays a different role in the immune system. All are produced by plasma cells. There is a constant amount of many, many different immunoglobulins in the body but in response to an infection, B-lymphocytes are converted into plasma cells that then make antibodies that uniquely target that particular infection. After the infection is cleared, the number of these plasma cells fall with the result that the level of those antibodies targeting a specific infection also fall.
- IgG is the most abundant immunoglobulin in the blood, accounting for 75% of blood immunoglobulins, and is the main workhorse antibody in the blood to fight bacteria and viruses that have entered the body. New IgG is produced about 1 – 3 weeks after the start of an infection. It is the only type of immunoglobulin that crosses the placenta. It has a half-life of 23 days.f-
- IgM is also produced by B-lymphocytes and released into the blood. It accounts for 10% of blood immunoglobulins. It is produced faster than IgG after an infection, generally in 5 – 10 days. It is also used to combat bacteria and viruses. It has a hallife of 7 days.
- IgA is the second most abundant immunoglobulin in the blood, accounting for 15% of blood immunoglobulins. However, secretory IgA is also produced in the mucosal lining that forms the surface of the airways and the gastrointestinal tract. Because of this, IgA is overwhelmingly the most abundant immunoglobulin in the mucus of the lungs and nose. As a result, IgA is the most abundant immunoglobulin in the body, when considering both the amount found in the blood as wells the amount found in other parts of the body. IgA is used to fight bacteria and viruses and secretory IgA in mucus can fight these pathogens before they enter the body. It has a half life of 5.5 days. There are two types of IgA – IgA1 is found in the respiratory tract and IgA2 is found in the gastrointestinal tract.
- IgE is used by the immune system to fight parasites, such as the worm Strongyloides. It is also involved in allergies. It is not involved in the defense against viruses. It has a half life of 2 days.
- IgD is only present in very tiny amounts in the blood and its function is not well understood.
Viruses usually enter the body either through the respiratory tract or the gastrointestinal tract. In these tracts, viruses first have to pass through epithelial membranes layered with mucus. The main class of antibodies in mucus is IgA and thus IgA is the more important antibody in the initial protection against respiratory viruses. Mucosal IgA can stop some infections altogether if there is enough IgA to bind all of the individual viruses that are inhaled. Even if a few viruses evade mucosal IgA and get into epithelial cells and into the bloodstream, the numbers of individual viruses are low, giving the adaptive immune system a chance to rev-up blood antibody production and defeat the infection before the virus can replicate into large numbers inside of the body.
IgA levels protect against COVID
One of the ways scientists learn about the roles of different immunoglobulins is by studying people who are born with deficiencies of different immunoglobulins. Selective IgA deficiency is the most common of these immunoglobulin deficiencies and occurs in somewhere between 1 in 200 and 1 in 1,000 Americans. The curious thing about IgA deficiency, however, is that two-thirds of patients are asymptomatic. In about one-third, IgA deficiency confers a greater risk of sinusitis and pulmonary infections. IgA deficiency can also cause increased susceptibility to allergies. However, there is evidence that IgA deficiency plays a role in defending the body against COVID infection. The COVID virus enters the body through the nose and then first infects the epithelial cells lining the respiratory tract by crossing through the airway mucus layer. Because IgA is the most important anti-viral defense in mucus, it follows that lower levels of IgA could increase the risk for COVID.
- A 2022 study in the Japanese Journal of Infectious Disease found that patients with selective IgA deficiency were 7.7-times more likely to have severe COVID infection than patients with normal IgA levels.
- A 2022 study in the Journal of Clinical Immunology found that patients with severe COVID infection had lower serum levels of IgA than those with less severe COVID infection and healthy persons.
- A 2023 study in The Lancet Infectious Disease found that healthcare workers who had detectable anti-COVID IgA in nasal mucus samples after vaccination had a lower risk of later getting a COVID infection than those healthcare workers who did not have detectable anti-COVID IgA in nasal mucus after vaccination.
- A 2023 study in the Journal of Allergy and Clinical Immunology Practice found that patients with selective IgA deficiency were more likely to get initial COVID infections and were more likely to have recurrent COVID infections than persons with normal IgA levels.
- IgA levels in respiratory secretions falls as people get older. A 2021 study in the Journal of Pharmacy & Bioallied Sciences found that salivary IgA levels fall after age 60. One possible explanation for the greater risk of severe COVID in the elderly could be from low mucosal IgA levels compared to younger persons.
Current mRNA vaccines have less effect on IgA
Given that secretory IgA in mucus appears to be an important component of the immune system’s defense against COVID, it follows that the effectiveness of vaccines against COVID depends in part on the ability of those vaccines to produce anti-COVID secretory IgA in the airways. Although current intramuscular mRNA vaccines are very good at stimulating anti-COVID IgG antibodies in the blood, they are not as effective in producing anti-COVID IgA antibodies in respiratory secretions.
- A 2022 study in in the journal Frontiers in Microbiology found that anti-COVID IgA was detectable in throat swabs 4 days after infection with COVID and in the blood 10 days after infection. However, after an intramuscular mRNA COVID vaccine, throat swabs were negative for anti-COVID IgA indicating that COVID infection causes the body to make IgA in respiratory secretions more effectively than COVID vaccination.
- A 2022 study in the journal Nature found that anti-COVID IgG and IgA was detectable in the saliva after the first dose of an mRNA COVID vaccine. After the second dose IgG antibody levels were boosted but IgA levels were not boosted. In fact, only 30% of subjects had detectable anti-COVID IgA in the sputum after the second dose of vaccine.
- A 2023 study in The Lancet eBioMedicine found that patients with COVID infection had high levels of anti-COVID IgA in both blood and nasal secretions for 12 months after infection. Subsequent vaccination caused an increase in blood IgA but did not cause an increase in nasal secretion IgA.
- A 2023 study in The Journal of Allergy and Clinical Immunology: Global found that after intramuscular mRNA vaccination, there was a significant increase in anti-COVID IgA and IgG in the blood but only a minimal increase in anti-COVID IgA in nasal secretions.
- A 2023 study in The Lancet Microbe found that anti-COVID IgA levels in nasal secretions did not increase substantially after booster mRNA vaccinations whereas IgG levels did increase.
How can we improve COVID vaccines?
For decades, physicians have written off IgA deficiency as having minimal, if any, clinical significance. But evolutionary science demonstrates that proteins that are unnecessary for the survival of a species eventually go away. It takes a lot of energy and nutrients to produce these proteins and individuals who do not need to expend energy and nutrients for unnecessary proteins can use that energy and nutrients for other functions, giving that individual a survival advantage. Taking into account both blood and secretory amounts, IgA is the most abundant immunoglobulin in the body. Even if we do not fully understand its functions, for the human body to expend so much energy and nutrients on IgA production, it must be important. Given the enormous amount of IgA found in respiratory mucus, it follows that its importance is in defense of inhaled viruses and bacteria.
The lungs have a huge surface area. If you were to lay out the surface of all of the bronchi, bronchioles, and alveoli in a person’s lungs, it would cover an area the size of a half of a tennis court. That surface area is exposed to the outside environment with every breath we take. COVID vaccines that result in a high level of anti-COVID IgA antibodies in the respiratory mucus should give the best protection against COVID infection. These IgA antibodies would be able to bind and destroy COVID viruses before those viruses enter the respiratory epithelial cells and cause infection. Vaccines that only increase antibodies in the blood but not in the respiratory mucus will not reduce the chances of getting infected but only reduce the severity of infection once it occurs.
To use an analogy, if you are trying to defend your country against an invading army, you are better off posting your defensive troops at your border, rather than trying to fight your battles in the interior of the country after the invaders have already crossed your borders.
So, how can we engineer vaccines to cause a robust secretory anti-COVID IgA response? The answer may be to give inhaled vaccines. This would potentially stimulate production of secretory IgA in the airways, where it is needed for the initial defense against COVID. Indeed, it may be that we need both inhaled vaccines to produce secretory IgA to protect against initial infection and intramuscular vaccines to produce blood IgG antibodies to protect against severe infection. The COVID virus enters our bodies in droplets and aerosols – it only makes sense that we should create vaccines that are also administered by droplets and aerosols.
Research is now being done to create inhaled COVID vaccines. At the Ohio State University College of Veterinary Medicine, researchers recently published their work in hamsters using an intranasal live-attenuated mumps virus containing the COVID spike protein. They found that this vaccine was highly effective in generating anti-COVID mucosal IgA and completely protected these hamsters from COVID infection. Subcutaneous administration of this live-virus vaccine was also effective. The MMR vaccine currently in use in pediatrics uses this same attenuated live-virus approach. There are currently phase 1 and phase 2 clinical trials underway in the U.S. and abroad using intranasal COVID vaccines.
The current generation of intramuscular mRNA vaccines have done what was most needed in the first years of the pandemic – they prevented people who were infected with COVID from dying of COVID. The next generation of vaccines should be designed to keep people from getting infected altogether. The key to this goal may be secretory IgA.
October 6, 2023