Popular understanding of how viruses work split immunity into four categories:

  1. Virus doesn't affect humans at all
  2. No immunity - will get worst possible infection, seems to be the case with COVID-19
  3. Partial immunity - you get sick, but it won't kill you - happens with flu mutations
  4. Full immunity - very hard to get sick - measles is an example

For #2 and #3 we could expect to find antibodies in the bloodstream proving that this person has partial or full immunity. But is it possible for some people to be resistant to a virus without having the corresponding antibodies in their bloodstream? And if so, how could their immunity be proven?

  • Too much in the way of antibodies can actually be a bad thing (so there's a 5th category). It's still in dispute why the 1918 influenza was so deadly, but one hypothesis (based on animal studies) is that in some groups the immune system "overreacted" aka the "cytokine storm" hypothesis healthline.com/health/1918-flu-pandemic-facts.
    – Fizz
    Apr 11, 2020 at 6:38
  • (Aside: even having that animal study conducted and published [in 2007] was fairly controversial.) Also, it's not the only virus known to do that "The research suggests that 1918 flu might work in a similar way to other viruses, such as West Nile, that can also cause a massive auto-immune reaction."
    – Fizz
    Apr 11, 2020 at 6:49

3 Answers 3


Antibody production is part of the adaptive immune response but the first line of protection against viruses and bacteria is the innate immune response which is cell based, and involves the release of cytokines, interferons, as well as direct cellular attack of infected cells.

Interestingly a recent study showed that some younger patients with milder symptoms had very low to neglible neutralizing antibody production after confirmed Covid-19 suggesting that their innate immunity was primarily responsible for fighting the virus.

Huang said 10 of the patients in the study had an antibody presence so low it could not even be detected in the laboratory.

These patients experienced typical Covid-19 symptoms including fever, chill and a cough, but might have beaten back the virus with other parts of the immune system such as T-cells or cytokines.


  • So people with 0 antibodies are more protected because the first barrier against the virus would be the innate immune response? And people having antibodies already, have 'wasted' their first protection (innate immune system)? Apr 11, 2020 at 14:51

The immune response to viruses involves multiple branches of the immune system. There are the innate and adaptive branches, and within the adaptive response, there are cell-mediated and antibody-mediated components. Different pathogens activate slightly different versions of the immune response. For example, cell-mediated immunity appears to be particularly important for protection against varicella zoster virus (VZV), and antibody titer is not necessarily reflective of immune status. In studies of the VZV vaccines, CD4+ T cells targeted to VZV are measured in addition to antibody titers.

A couple additional caveats about relying on antibody titers to determine protective immunity--

Detection limits: It's important to consider the detection limit of the test being used. Undetectable antibody and absent antibody are not necessarily the same.

Antibody target: Many antibodies may be generated to a virus, but only a subset of these will be effective at mounting an effective immune response to the virus. Detection of an antibody does not equate protective immunity.


The answer is yes, there are "general features" of the immune system and basically of our genome that combat many different pathogens, but also there are very specialized ones, only useful against a few. To make the matter more complicated, recent research has found that the immune system "cross-learns" from infections (and possibly from vaccines as well).

First on "purely genetic" defences, some alleles confer enhanced resistance to some viruses. Quoting a 2007 review

Some proteins that are required for surviving viral infection are used to combat many other microorganisms as well. In mammals, for example, myeloid differentiation primary-response gene 88 (MyD88), a Toll-like receptor (TLR) adaptor molecule, is required for effective resistance to herpesviruses, Toxoplasma gondii and other organisms that have few obvious features in common. By contrast, some defences that evolved recently are matched against specific microorganisms and may operate only within a single host species. For example, the Ly49H receptor expressed by mouse natural killer (NK) cells seems to recognize only mouse cytomegalovirus (MCMV), and does so only in some strains of mice, as the receptor-encoding gene has been deleted in other strains. More tentative defences are also apparent. For example, mutational abrogation of the human CC-chemokine receptor 5 (CCR5) protein offers strong protection against infection with HIV, but the most common protective allele has not been driven to fixation in humans. And it is likely that many other potential resistance mechanisms remain to be exploited in mammals.

Some protective antiviral systems are cell autonomous, whereas others depend on multiple specialized cell types that interact both with the infected cells within the host and also with one another. In mammals, the response to viral infection overlaps substantially with the response to bacteria, using some of the same sensing, signalling and effector mechanisms. In insects, there is a greater reliance on cell-autonomous defence, and new advances must be made in defining the pathways that are involved. [...]

Resistance to viral infection comes at a definite cost. In mammals, the cellular systems that confer protection against viruses are also capable of causing autoimmunity. This may be seen as a reflection of three facts. First, viruses have imposed a need to distinguish between host nucleic acid and foreign nucleic acid — a challenge that has been met by mammals in the large part, but not completely. Second, viruses certainly contributed to the evolution of adaptive immunity, upon which autoimmunity is predicated. And third, some of the elements of innate immunity that support autoimmune disease (among them the |IFNs and cells that produce them) evolved largely to combat viruses.

Beyond this "fixed"/innate defense system, there's another more recently discovered one that can be considered "intermediate" (i.e. between innate and the classical def of "adaptive immunity"):

Protection against reinfection has been reported not only in plants and invertebrates that do not have adaptive immunity (4), but also in mammals, with old and new studies demonstrating cross-protection between infections with different pathogens (5). These studies have led to the hypothesis that innate immunity can be influenced by previous encounters with pathogens or their products, and this property has been termed trained immunity or innate immune memory.

(In fact this discovery has led some to propose a reconsideration of the immune system dichotomy.)

Also, you assume (in your #2) that COVID-19 outcomes are always better with more immune response, but that might not actually be the case (harking back to a hypothesis about the 1918 flu deadliness):

Some of the earliest analyses of coronavirus patients in China suggested that it might not be only the virus that ravages the lungs and kills; rather, an overactive immune response might also make people severely ill or cause death. Some people who were critically ill with COVID-19 had high blood levels of proteins called cytokines, some of which can ramp up immune responses. [...]

A combination of damage from both a virus and the immune response to it is not uncommon, says Rafi Ahmed, a viral immunologist at Emory University in Atlanta, Georgia. The effects of 'hit-and-run' viruses such as norovirus, which make people sick almost immediately after infection, are more probably due to the virus itself, he says. By contrast, people infected with viruses such as coronavirus do not show symptoms until several days after infection. By then, collateral damage from the immune response often contributes to the illness.

Based on the convergence of epidemiological data and animal research, the auto-immune response is suspected to have been a (probably more significant) factor in 1918:

unlike contemporary influenza strains, which typically affect the very young and the elderly most severely, the 1918 influenza pandemic was mostly fatal in young adults, who generally possess more robust immune systems.

The work of Kobasa et al. substantiates the findings of Kash et al., who showed in mice that the 1918 virus triggered a vigorous innate immune response that was linked to fatalities. Although the mechanisms of tissue destruction were not addressed in either study, the work clearly demonstrates the vital function of early innate immune defences in controlling the virus. It seems that the pandemic 1918 virus had a genetic composition and rapid replication kinetics that may have resulted in an excessively vigorous innate immune and inflammatory response that contributed to severe tissue damage, disease and death.

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