Immune response to SARS-CoV-2

In response to the SARS-CoV-2 coronavirus, the body produces specific antibodies, b cells, and CD4+ and CD8+T cells. Upon recovery, approximately 90% of these virus-specific cells die, and 10% are preserved as long-lived memory cells.

CD4+ memory T cells (t helper cells) help activate pathogen-specific memory B cells and secrete cytokine signaling molecules, including Ifny, to activate innate immune cells. CD8+ memory T cells (t-killers) can kill virus-infected cells directly by delivering cell-destroying molecules. Immune memory cells help the body quickly get rid of the virus, prevent disease, and reduce the likelihood of transmission of the virus.

SARS-CoV-2 uses a structure at the end of its spike protein (S) to infect cells and multiply. This structure-the receptor-binding domain (RBD) – binds to the ACE2 receptor of a human cell, and the virus enters the cell.

Most people infected with SARS-CoV-2 produce S- and RBD-specific antibodies in the primary immune response. RBD-specific monoclonal antibodies (derived from copies of a single B-lymphocyte) can neutralize the virus in vitro and in vivo.

The final stage of B-lymphocyte development is plasma cells. These are the central cells that produce antibodies in the human body. If specific antibodies to RBD are expressed by long-lived plasma cells (LLPC) or pathogen-specific memory B cells (MBC), these antibodies can likely protect against re-infection with the SARS-CoV-2 coronavirus.

T cells reduce the severity of COVID-19

Neutralizing antibodies are generally not associated with a reduction in the severity of COVID-19. In non-human primates, the production of neutralizing antibodies protects against re-infection with SARS-CoV-2 or SARS-CoV.

The introduction of neutralizing antibodies before infection simulates re-infection. It effectively limits infection of the upper and lower respiratory tract, including the lungs, and reduces coronavirus symptoms in animal models.

Administration of neutralizing antibodies after infection in humans has a more limited effect on COVID-19. That confirms the significant role of T cells in controlling and clearing the body of SARS-CoV-2.

Studies of acute and convalescent patients with COVID-19 have shown that T-cell responses are associated with the reduced disease. SARS-CoV-2-specific CD4+ and CD8+ T cells may play an essential role in controlling and resolving primary SARS-CoV-2 infection.

To better understand the persistence of protective immunity against COVID-19 generated by primary SARS-CoV-2 infection, further comprehensive study of antibodies, memory B cells, CD4+ and CD8+ memory T cells is important.

Not only antibodies protect against COVID-19

Although immunological memory is a source of long-term protective immunity, direct conclusions about protective immunity cannot be made based on a quantitative assessment of circulating antibodies to SARS-CoV-2, memory B cells, CD8+ and CD4+ T cells, since the mechanisms of protective immunity against SARS-CoV-2 or COVID-19 in humans have not been determined. However, some reasonable interpretations can be made.

Antibodies are the only component of immune memory that can provide genuinely sterilizing immunity.

Immunization studies on non-human primates have shown that circulating titers of neutralizing antibodies ~ 200 can provide sterilizing upper respiratory tract immunity against a relatively high dose of SARS-CoV-2 virus and neutralizing titers ~ 3400 can provide sterilizing immunity against a very high dose of the virus.

While only neutralizing antibodies with a high titer provide sterilizing immunity against viruses, successful protection against clinical disease or death can be achieved using several other adaptive immune memory scenarios.

CD4+ and CD8+ memory T cells, as well as memory B cells that produce neutralizing RBD antibodies, can limit SARS-CoV-2 in the upper respiratory tract and oral cavity and minimize the severity of COVID-19 to the common cold or asymptomatic disease.

In humans, SARS-CoV-2-specific CD4+ T cells and CD8+ T cells are associated with a decrease in COVID-19 severity in ongoing SARS-CoV-2 infection, and rapid antibody formation is associated with a significant reduction in viral load in acute disease over 14 days. These findings are consistent with the hypothesis that t cells and memory B cells can significantly limit the spread of SARS-CoV-2 or viral load, leading to a significant reduction in the severity of COVID-19 disease. The likelihood of such outcomes is closely related to the kinetics of infection since B and T memory cells’ responses can take 3-5 days to respond successfully to infection.

Given the relatively slow course of severe COVID-19 in humans, there is a large window of time for immune memory to contribute to protective immunity against pneumonia, severe or fatal repeated COVID-19. The presence of neutralizing antibodies during exposure to SARS-CoV-2 would blunt the initial infection’s size and could further contribute to limiting the severity of COVID-19.

Heterogeneity of immune memory to SARS-CoV-2 and risk of re-infection

American scientists studied immune memory in 185 people aged 18 to 81 years with asymptomatic, mild, moderate, and severe COVID-19. Most patients had a mild case of COVID-19 that did not require hospitalization. 92% of the study participants were never hospitalized due to COVID-19. 7% of the participants were hospitalized; some of them required treatment in the intensive care unit. It corresponds to the severity distribution of COVID-19 in the United States. The majority of participants (97%) reported symptoms of the disease. Most participants gave a blood sample once between 6 and 240 days after the onset of symptoms. 41 participants gave a blood sample more than 6 months after the onset of symptoms. 38 participants provided 2-4 repeated blood samples over several months.

Features of immune memory to SARS-CoV-2:

  • The titers of circulating antibodies in severe cases of COVID-19 were higher than in mild cases, which is consistent with data from other studies.
  • There were no differences in B-and T-cell memory between hospitalized and non-hospitalized COVID-19 cases.
  • Overall, men had higher levels of IgG antibodies against spike protein (S) and nucleocapsid (N) and RBD than women. Higher levels of S IgG in men were also observed in the convalescent group.
  • In contrast, there were no differences between men and women in the frequencies of b and t memory cells to SARS – CoV-2.

Thus, the heterogeneity of immune memory to SARS-CoV-2 is not related to the gender or severity of COVID-19 disease.

The magnitude of the antibody response against SARS-CoV-2 is very heterogeneous in different people. Heterogeneous initial antibody responses are not reduced to a homogeneous circulating antibody memory. This heterogeneity is the main feature of immune memory to SARS-CoV-2. For antibodies, the responses cover a ~ 200-fold range.

The source of the heterogeneity of immune memory to SARS-CoV-2 is unknown and deserves further study. This heterogeneity may result from a low cumulative viral load, resulting in a very minor or transient infection that causes a weak adaptive immune response.

As a result of the immune response’s heterogeneity, we can expect that at least a part of SARS-CoV-2 patients with insufficient immune memory will be relatively quickly susceptible to re-infection.

How long does immunity to coronavirus last after the natural course of the disease

Scientists have suggested that 5 components play an essential role in protective immunity: RBD IgG, IgA RDO, RDO B-memory cells, SARS-CoV-2-specific CD8+, and CD4+ T cells.

Results of the study on 185 patients showed that SARS-CoV-2 demonstrates different kinetics:

  • 1–2 months after symptom onset, the majority (59%) of COVID-19 cases were positive for all five components of immune memory.
  • There were incomplete immune responses. Some people had no CD8 + T cell memory or an inadequate RBD IgA antibody response.
  • By 5+ months after COVID-19, the proportion of people positive for all five immune memory components dropped to 40%. However, 96% of people were still positive for three out of five SARS-CoV-2 immune memory responses.
  • Peak IgG antibody titers were persistent, with a moderate decline of 6-8 months after symptom onset. RBD IgG titers were potentially equally stable.
  • 5+ months after the onset of symptoms, almost all people were positive for S and RBD IgG antibodies to SARS-CoV-2.
  • Memory B cells specific for the S spike protein or RBD have been found in almost all cases of COVID-19, with no apparent half-life 5+ months after infection.

B cell memory of some other infections is long-lasting: 60+ years after smallpox vaccination, 90+ years after a flu infection.

The memory T cell half-life observed for 6+ months after symptom onset in this study (~ 166-271 days for CD8 + and ~ 96-174 days for CD4 + T cells) is comparable to the 123-day half-life for CD8 + T – memory cells after immunization against yellow fever. The half-life of CD4 + smallpox memory T cells is ~ 10 years. There is a known case of detecting T cells to SARS-CoV 17 years after the initial infection. These data indicate that T cell memory may reach a more stable plateau or slower decay phase later than the first 6 months after infection.

Immune memory, consisting of at least three immunological components, was measured in ~ 90% of subjects ≥ 5 months after symptom onset. It indicates that sustained immunity against recurrent COVID-19 is possible in most people.

Is immunity to SARS-CoV-2 preserved after COVID-19 in a mild form?

The first wave of the immune response is short-lived, ineffective plasmablasts secreting antibodies. The body then generates highly efficient memory B cells (MBC) and long-lived plasma cells (LLPC) that secrete antibodies. LLPCs can maintain detectable serum antibody titers from months to many years, depending on the specific viral infection. It is imperative to distinguish the first wave of declining plasmablast-derived antibodies from the later wave of resistant LLPC-derived antibodies, which can neutralize subsequent infections, potentially for life.

Populations of activated cells of innate and adaptive immunity increase in the blood during the primary response to SARS-CoV-2 infection. When an acute viral infection has passed, most of these inflammatory cells die or become memory cells.

Scientists at the University of Washington (Seattle, Washington, USA) evaluated immune responses in patients with mild COVID-19 one and three months after the onset of symptoms.

To determine if immune memory cells are formed after COVID-19 with mild symptoms, scientists collected plasma and peripheral blood mononuclear cells from 15 people who had recovered from COVID-19. The first blood sample was taken ≥ 20 days after a positive PCR test for SARS-CoV-2 and an average of 35.5 days after the onset of symptoms. The viral load decreases approximately 8 days after the onset of symptoms, so at this point in time, the primary immune response will decline, and early immune memory will form. A second blood test was collected on average 86 days after the onset of symptoms to assess immune memory cells’ number and quality.

The study found that mild COVID-19 induces persistent neutralizing IgG antibodies to SARS-CoV-2. For at least 3 months after symptom onset, participants had LLPCs that maintain detectable levels of neutralizing antibodies S and RBD IgG against SARS-CoV-2.

SARS-CoV-2 infection induces resistant functional S-reactive CD4 + memory T cells. Memory CD4 + T cells produce cytokines within hours of activation, whereas naive T cells require several days. The CD4 + memory T cells, specific for SARS-CoV-2, retain their ability to help B cells even three months after the onset of symptoms.

CD8 + memory T cells can kill virus-infected cells through targeted expression of cytokines and cell-damaging molecules. Both CD4 + and CD8 + SARS-CoV-2 specific memory T cells are conserved and capable of producing effector cytokines three months after symptom onset in COVID-19 patients with mild symptoms.

RBD-specific memory B cells induced by SARS-CoV-2 infection can produce neutralizing antibodies against the virus and may help protect against re-infection with SARS-CoV-2.

The study demonstrated increased levels of RBD IgG antibodies, which are formed and persist for at least 3 months after infection with SARS-CoV-2.

Immune memory for SARS-CoV-2 is formed and retained after a mild form of COVID-19 for at least 3 months. Memory T cells have signs of protective antiviral immunity. While antibodies reveal the contribution of long-lived plasma cells (LLPC), functional virus-specific memory of B- and T-lymphocytes may also be the key to protective immune memory.

Immunity to SARS-CoV-2 in asymptomatic coronavirus infection

Despite the ability of asymptomatic people who got rid of SARS-CoV-2 to control the infection effectively, it was hypothesized that their antiviral adaptive immune response was reduced. This hypothesis is supported mainly by measurements of specific antibodies to SARS-CoV-2 and the number of B cells.

Antibodies and T cells work together to reduce the spread of the virus in the body and destroy the pathogen. However, a protective immune response can also trigger pathological processes characterized by localized or systemic inflammatory responses. Inflammation and tissue damage may result from the killing of infected cells by virus-specific antibodies and T cells, or the release of inflammatory mediators produced by infected cells and activated myeloid cells. In severe cases, high systemic levels of inflammatory cytokines and activated monocytes coexist with virus-specific antibodies and T cells. Thus, the question remains as to whether virus-specific antibodies and T cells preferentially cause protection or damage.

The effectiveness of virus-specific T cells in eliminating pathogens depends on a delicate balance between their antiviral and inflammatory properties. SARS-CoV-2 specific T cells in people who have cleared SARS-CoV-2 infection without symptoms may exhibit non-pathological but protective characteristics.

Scientists from Singapore compared the number and function of SARS-CoV-2-specific T lymphocytes in a group of asymptomatic individuals (85 people) and patients with symptoms of COVID-19 (76 people) at different points in time after the formation of antibodies. Participants were selected from among workers who lived in densely populated dormitories and donated blood when they were hired.

Scientists quantified T cells reactive to viral proteins: N (nucleocapsid), S (spike protein), and M (virus membrane), and measured the amount of cytokine secretion: IL-2, IFN-γ, IL-4, IL- 6, IL-1β, TNF-α and IL-10 in whole blood after activation of SARS-CoV-2 T cells.

Research has shown that:

  • In the early stages of recovery, T-lymphocytes’ frequencies specific for various SARS-CoV-2 proteins were similar in asymptomatic and symptomatic individuals.
  • SARS-CoV-2-specific T cells are present in all asymptomatic people with antibodies to the coronavirus.
  • The frequency of SARS-CoV-2-specific T-lymphocytes, detected 2-3 months after asymptomatic infection, was lower than in COVID-19 patients at a similar time after infection and identical to that found in those who recovered from COVID -19 people 6 months after infection.
  • In asymptomatic individuals, high levels of the pro-inflammatory cytokines IFN-γ and IL-2 and intermediate levels of the pro-inflammatory cytokines IL-6, TNF-α, IL-1β, and the anti-inflammatory cytokine IL-10 were observed. In contrast, symptomatic individuals had low levels of IFN-γ and IL-2 and very high levels of IL-6, TNF-α, IL-1β, and IL-10.

The overall magnitude of T cells’ response against various structural proteins is the same in both asymptomatic individuals and patients with COVID-19. T cells induced by asymptomatic infection appear to secrete more IFN-γ and IL-2 and induce more joint production of pro-inflammatory and regulatory cytokines than T cells from symptomatic COVID-19 patients.

Thus, the ability to elicit a significant virus-specific T cell response is not necessarily related to symptom severity. Asymptomatic people infected with SARS-CoV-2 are not characterized by weak antiviral immunity. On the contrary, they develop a stable and highly functional virus-specific cellular immune response, which protects the body and does not cause any apparent pathologies.

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