Cell-Mediated and Innate Immunity Against SARS-CoV-2: What is Known

January 26, 2022

Titers of neutralizing antibodies (nAbs) against SARS-CoV-2 have proven a reasonable predictor of protection against infection and disease. However, T cell responses (CD8+ and CD4+), innate immune mechanisms, and Fc-mediated cellular cytotoxicity can also provide protective immunity against the virus.

T cells

The role of T cell activities in correlates of protection is less well understood than that of nAbs, mostly because they are more difficult to measure. They are likely to be important with omicron, as the ability of nAbs from vaccination or previous infection have shown seriously diminished effectiveness. Furthermore, while nAb levels decrease gradually, memory T cells responses are more durable, lasting 17 years following infection with SARS-CoV-1[1]. Early appearance of T cells secreting IFN-γ in response to ORF7/8, ORF3a, nucleoprotein (N), membrane (M), and spike (S) proteins correlates with milder disease and more rapid viral clearance[2], suggesting a protective role for T cells. Protection of exposed health care workers (who remained uninfected but had possible signs of abortive infection) was correlated with high levels of T cell activity against the viral replication complex machinery[3], possibly derived from previous infections with seasonal coronaviruses. Another study that drew similar conclusions demonstrated T cell activities against non-spike proteins[4]. Interestingly, no correlation was observed with S protein-specific T cell activities

Immune Responses

The initial immune responses to SARS-CoV-2 are the first host defense. Activation of innate immunity plays an important role in developing adaptive immunity. Several viral proteins are involved in blunting these responses. For example, the alpha variant overexpresses N, Orf9b and Orf6, all of which are innate immune antagonists and inhibit interferon expression, in airway epithelial cells[10]. Delta and omicron have similar mutations in N and Orf9b. An effective antiviral response requires a rapid expression of interferon, and SARS-CoV-2 infection delays this expression, rendering it largely ineffective[11]. From this it seems likely that SARS-CoV-2 is vulnerable to interferon-linked elements of innate immunity. Two reports are consistent with this idea. Children, who have a substantially reduced risk of infection and severe disease, have elevated basal expression in the upper airway of RIG-1 and MDA5, patten sensors involved in innate immune responses[12]. This results in a stronger innate immune response than occurs in adults.

There is also a reduced incidence of infection and disease in people who are supertasters”[13]. Supertasters are homozygous for an allele of the T2R38, gene, a receptor for bitter taste. T2Rs help regulate upper airway immunity[14] by producing antimicrobial peptides and NO in response to agonists, suggestive of a protective mechanism. Yet another antiviral activity against SARS-CoV-2 is mediated by RIG-1 in an interferon-independent manner[15]. RIG-1 recognizes the 3’ untranslated region of the viral RNA and blocks the first step of RNA replication, inhibiting viral replication in human lung cells. It is not clear how to translate these observations into a protective modality, but it has been suggested that live attenuated vaccines (such as the oral polio vaccine), which elicit a broad innate immune response lasting some months, might provide short term protection against SARS-CoV-2[16].

Omicron is clearly able to overcome immune barriers to infection. Also, this variant is far more transmissible than others, making it an hyper transmissible variant.

Its ability to evade immune responses seems a significant factor favoring increased reinfection in vaccinated and naturally infected people. This has been amply demonstrated in reduced protection from infection resulting from reduced activities of neutralizing antibodies against the omicron variant

In spite of its enhanced contagiousness, omicron appears to have reduced pathogenicity in infected people[9] and this phenomenon has recapitulated in animal models.

Perhaps the least well studied of the immune responses to SARS-CoV-2 are those that depend upon the Fc region (non-antibody-binding) of antibodies and which can result in the killing of infected cells and viral clearance, although they can also contribute to inflammation. These combine aspects of adaptive and innate immunity and are regulated by antibody subclass and by glycosylation of the Fc region[17]. There are three types of these mechanisms: antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent complement deposition (ADCD), and antibody-dependent cell-mediated phagocytosis (ADCP). A recent report showed differences among these activities in infected people with mild vs severe disease[18], suggesting that they contribute to infection outcomes. Antibodies to the S1 protein and its receptor binding domain (RBD) from more severely ill patients had higher ADCD but lower ADCP than those from non-severely ill patients. Higher ADCD was associated with higher systemic inflammation, suggesting ADCD as a contributor to pathogenesis. ADCC correlation with disease was more complex. Anti-S1 antibodies from more severely ill patients showed higher levels of ADCC than did those from less severely ill patients. However, the opposite was true for anti-RBD antibodies. Clearly there is a complex interplay between Fc-mediated antibody activities and disease outcomes that needs to be more clearly understood, but which constitute an important determinant in outcomes of infection. This can probably be said, however, about all the mechanisms of immunity that do not involve neutralizing antibodies.


The mutations in the omicron S protein results in greatly reduced neutralization by antibodies, but many potential T cell epitopes are unchanged[5-7]. In fact, mRNA vaccines have shown to induce polyfunctional CD4+ and CD8+ T cell memory responses that peaked 2 weeks after the second dose of the vaccine and contracted at 6 months after vaccination. Despite reduced nAB levels, the vaccines provide protection from severe illness and hospitalization from the omicron variant. Clearly, boost (a third dose) vaccination greatly enhances protection against omicron. Since the emergence of SARS-CoV-2, the scientific community has made great progress on natural infection induced and vaccine induced immunity. This knowledge has been vital to prepare the next generation of vaccines by balancing B and T cell mediated immune responses. For future pandemic preparedness, we will need universal vaccines against various coronaviruses and emerging coronaviruses with lasting immunity.


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