Humoral Response
Detecting a humoral response against SARS-CoV-2 has been the focus of attention to developing faster and more accurate diagnostic tools. A study assessing the presence of IgA, IgM, and IgG against SARS-CoV-2 in infected patients found that IgA levels begin to rise in the first seven days after the onset of symptoms and continue increasing until it stabilizes near the 14th day after the onset of symptoms. Additionally, IgM production appears as early as IgA, the antibody titration in the first seven days after the onset of symptoms was very low, starting to increase only from the eighth day, reaching a plateau after the 14th day. The average time of appearance of specific IgG against SARS-CoV-2 starts 14 days after the appearance of symptoms and grows exponentially until the 21st day (197).
These data corroborate the disease stages proposed by Lin et al. (6) (presented in the introduction), and the changes in the immune response present in the disease. The early appearance of IgA results from the first contact of the virus with the individual’s mucosa at the moment of contagion and continues to increase until the acute phase. Despite viremia and symptom onset, IgM levels only begin to rise from the eighth day after symptom onset, indicating anergy in the immune response during this period, perhaps caused by dysfunction in antigen-presenting cells, such as dendritic cells, and also by reducing the amount of activated T helper cells, which play a central role in triggering the immunity acquired by the activation and clonal expansion of B lymphocytes, in addition to the formation of germinal centers and generation of plasma cells that produce high affinity and avidity antibodies (198, 199).
The appearance of IgG near the third stage of the disease may be related to the clinical evolution of patients and those who fail to establish an efficient immune response might be at risk of death. Interestingly, Guo et al. (197) found that approximately 22% of COVID-19 patients confirmed by RTq-PCR did not present detectable levels of IgM. Most of these individuals were tested in the first seven days after the onset of symptoms, therefore the lack of IgM can be justified by the delay in generating a humoral response against SARS-CoV-2. However, some critically ill patients followed for a longer period remained negative for IgM even 22 days after the onset of symptoms. As for IgG levels, some patients took 30 to 40 days after the appearance of symptoms to show some detectable level of IgG, suggesting a possible failure in the production of antibodies that may have contributed to the severity of the disease. It is possible that the generation of antibodies in more advanced stages of COVID-19 does not benefit the recovery process since most pathological mechanisms at this stage might be more related to the excess of inflammatory mediators than the presence of the virus itself.
In recovered patients, the magnitude of the production of neutralizing antibodies (nAb) against SARS-CoV-2 is positively correlated with the severity of the disease; while asymptomatic individuals have little or no capacity to produce nAb, individuals who recovered from severe cases of COVID-19 had robust nAb production. Also, these severe recovered patients showed an increase in B cell receptor (BCR) rearrangement, which may demonstrate that the effective production of nAb requires enhanced and prolonged BCR stimulation. Asymptomatic or mild symptomatic patients may possibly mount robust SARS-CoV-2 specific CD8 + T cell responses, which can provide protection by directly eliminating the target cells infected by the virus. However, due to the lack of immunity provided by nAb, these individuals might suffer from SARS-CoV-2 reinfection (200, 201).
In the same way, Zhang et al. (202) also demonstrated that patients who recovered from severe COVID-19 have high levels of BCR clonal expansion and B cell activation, indicating a more robust humoral response than patients with mild disease, thus asymptomatic individuals or those with mild COVID-19 probably have different cell and humoral responses than individuals who developed the severe form of the disease.
In an article published by Chen et al, the serum of 26 patients who recovered from COVID-19 were analyzed for the production of IgG anti-SARS-CoV-2 S1 protein antibodies. It was found that, despite the majority of patients presenting high IgG titers, only three individuals had antibodies that effectively neutralized the binding of the viral glycoprotein to the human ACE2 receptor. In addition, the authors successfully managed to clone two different neutralizing antibodies from these patients with the ability to inhibit virus-cell binding, opening up the potential for using them as a possible source of treatment for COVID-19 (203).
In theory, the production of specific neutralizing antibodies against SARS-CoV-2 should be able to combat the virus and reduce viral load. The production of immune memory verified in the blood of recovered patients has also been used to treat COVID-19 patients, as we will discuss further (204).