Immune through the pandemic

>> Modern immunology is a relatively young science. Antibodies were only discovered in 1890. The scientific understanding of the Spanish flu and COVID-19 is worlds apart. This makes it all the more astonishing how, during the COVID-19 pandemic, "immunological" misunderstandings in the public eye and among political decision-makers contributed significantly to misjudgments and restrictions. Without wishing to delve into the sociological background of this development, it may be helpful to address some key misunderstandings by name for addressing future pandemic challenges:

#1: Neutralizing antibodies in the blood are not a correlate of protection.
For viruses that attack us through the respiratory tract, the first problem is penetrating the mucus of the respiratory tract. Here, in the mucus of the respiratory tract, "neutralizing" antibodies can prevent infection if they bind to the SARS-CoV-2 receptor in such a way that it prevents binding to our cells. For some "experts" and many others, "neutralizing," "sterile" immunity—that is, protection against infection as such—was the only relevant immunity. Countless scientific publications have been published on "neutralizing" antibodies. There was talk of "immune escape" when a new variant of the virus was no longer "neutralized." Unfortunately, neutralizing antibodies from the blood were examined. Very few scientists have studied antibodies in the respiratory tract. They found that the antibodies there disappear within weeks and months after vaccination, but also after recovery from infection, even if they are still clearly detectable in the blood. The problem of "sterile" immunity is the transport of antibodies from the blood to the surface of the respiratory tract. How these transport mechanisms are activated is not well understood. This would be the key to effective adjuvants in a vaccine that provides long-term protection against infection. Perhaps we can learn from our microbial roommates, the bacteria of the microbiome. For example, the bacterium Streptococcus salivarius ensures that the neutralizing antibodies remain on the mucous membranes (1).
Clearly, our immune system isn't designed to provide long-term protection from infection, but rather to protect infected individuals from serious illness and death. For this "systemic" immunity, the neutralizing antibodies in the blood aren't so important. It's sufficient for antibodies to clump viruses together and mark them for immune cells. It's not for nothing that nature has equipped every antibody with at least two identical binding sites for the antigen: a prerequisite for clumping, which prevents individual viruses from infecting new cells. So:

#2: Non-neutralizing antibodies against SARS-CoV-2 are important for systemic immunity, protection against severe disease.

#3: Quality over quantity in antibodies.
Do we lose our immunity when antibodies in the blood decrease? We already knew this before the pandemic (2). In fact, it is not so much the quantity of antibodies that determines our immunity, but their quality. During an immune response, cells that process the viral antigen interact with the T and B lymphocytes of the immune system. B lymphocytes are activated when their antibodies bind to the antigen. During a (successful) immune response, the antigen decreases in quantity, and ultimately only those B lymphocytes whose antibodies recognize the smallest amounts of antigen are activated. During this "affinity maturation," extremely strongly binding antibodies are formed. Their quantity decreases, but they protect us effectively, and they still bind virus variants very well.
These immune reactions last half a year or more, not only for SARS-CoV-2 infections, but also for vaccination. Much longer than the actual disease itself. The amount of antibodies in the blood also decreases for this length of time. Afterward, however, they remain stable for many years. In the case of the first SARS virus, SARS-CoV, antibody levels in the blood of recovered patients have been stable for 17 years, from 2003/4 to 2020. This long-term, stable antibody production after the end of an immune reaction is based on the cells that secrete these antibodies, also called "plasma cells," settling in the bone marrow, where they survive in specific "niches" for many years. It should be mentioned in passing that the number of SARS-CoV-2-specific plasma cells in the bone marrow after recovery from the infection is approximately the same as after three Comirnaty vaccinations, and roughly corresponds to the number of plasma cells that produce tetanus-specific antibodies.

#4: Saturation of the immune system.
A common misconception: "If 'sterile' immunity is so short-term, you just have to get boosters more often to stimulate it again." This misunderstanding has led to drastic consequences, 2G/3G regulations, the shortening of the "recovered status" to a few months, and a debate about mandatory vaccination. The fact is, our immune system adapts to the pathogens in our environment. With frequent contact with the same pathogen, new immune reactions no longer occur, not even "sterile" immunity. Thus, protection against infection is over 80% shortly after the third vaccination with Comirnaty, and only 30% after the fourth vaccination. At least with vaccination, "more is more," not "more is enough," applies. After all, a strong imprinting of the immune system on a pathogen can also lead to us no longer responding as well to new, similar pathogens (3).

literature
1. Bondareva M., et al. Cell Host Microbe. (2023) doi: 10.1016/j.chom.2023.10.007.
2. Wheel break A, Chang HD. Nature.(2021) doi: 10.1038/d41586-021-01557-z
3. Kozlov M. Nature (2024) doi: 10.1038/d41586-024-02170-6