The severe acute respiratory coronavirus 2 (SARS-CoV-2) of the Coronaviridae family is the causative agent of the coronavirus disease 2019 (COVID-19) global pandemic that has caused greater than 6.5 million deaths from over 600 million recorded infections.

SARS-CoV-2 is closely related to SARS-CoV and the Middle East respiratory syndrome coronavirus (MERS-CoV), each of which led to epidemic outbreaks in 2002-2003 and 2013-2014, respectively, and are related to significant morbidity. Human infections have also been reported from other coronaviruses, resembling OC43, 229E, NL63, and HKU1, most of which manifest because the common seasonal cold.

Study: Latest insights into human immune memory from SARS‐CoV‐2 infection and vaccination. Image Credit: Kateryna Kon / Shutterstock.com

Background

SARS-CoV-2 enters the host by binding to angiotensin-converting enzyme 2 (ACE2) receptors on the surface of host cells through its receptor-binding domain (RBD) throughout the viral spike protein. ACE2 receptors are present within the cells of the respiratory tract, gastrointestinal tract, heart, and kidneys. 

Most individuals who contract SARS-CoV-2 experience mild respiratory symptoms. Nonetheless, patients with pre-existing comorbidities, resembling chronic obstructive respiratory disorder (COPD), obesity, asthma, and immunocompromised individuals, are at a greater risk of severe COVID-19. For instance, those with increased ACE2 expression or impaired immune function exhibit higher viral loads, infectivity, and poor viral control.

Scientists have studied human immune responses against SARS-CoV-2 infection. Recently developed technologies can detect, quantify, and phenotype immune memory cells. The emergence of SARS-CoV-2 variants of concern (VOCs) has emphasized the necessity for biomarkers able to quantifying the protection conferred by COVID-19 vaccines based on the initial Wuhan strain.

A recent Allergy journal study reviews current knowledge regarding the generation of immune memory responses and their durability post-infection and vaccination. The researchers also provide insights into immune memory for its ability to guard against emerging VOCs.

Methods for detecting SARS-CoV-2 immune memory cells

The adaptive immune system primarily relies on the motion of each T- and B-cells to elicit antigen-dependent and antigen-specific responses. After infection or vaccination, B- and T-cells that recognize a pathogen from prior exposure will respond, proliferate, and differentiate.

Thus, the cells of the adaptive immune system allow for the event of immunologic memory, comparable to the innate immune response that doesn’t have the capability for memory. The cells accountable for this subsequent response are memory B-cells (Bmem) and memory T-cells (Tmem).

Bmem are traditionally detected using enzyme-linked immunosorbent spot (ELISPOT), a particularly sensitive and rapid technique. Despite these benefits, ELISPOT is a time-consuming process that doesn’t provide any information on isolated B-cells that don’t recognize the antigen of interest.

One other approach that could be used to find out the antigen reactivity of Bmem or plasma cells is the immortalization of B-cell clones, which identifies the antibodies produced by a single B-cell clone. Nonetheless, this method is commonly time-consuming and labor-intensive, limiting its applicability in certain settings.

Antigen-specific B-cells may also be identified by labeling the antigen of interest and subsequently probing the cells for his or her reactivity to those antigens. This approach ensures a radical examination of the immunophenotype of those cells while also allowing the researchers to gather the cells at the tip of the experiment for further evaluation.

In comparison with B-cell evaluation, the assessment of SARS-CoV-2-specific T-cells is tougher, as they only recognize a peptide fragment of the unique antigen. Thus, researchers will use different assays to detect antigen-specific CD8+ and CD4+ T-cells.

Antigen-specific T-cells may also be assessed by stimulating peripheral blood mononuclear cells (PBMCs) with whole protein antigens to find out different T-cells produced by this response, as indicated by certain activation markers. These can include intracellular cytokines resembling interleukin 2 (IL-2), tumor necrosis factor α (TNF- α), and interferon γ (IFN- γ).

Antibody responses to SARS-CoV-2

Between seven to 10 days after SARS-CoV-2 infects cells, activated B-cells differentiate into plasmablasts. These plasmablasts subsequently induce the production of antibodies that typically goal the spike and nucleocapsid proteins of SARS-CoV-2 by 20 days following infection.

The quantification of neutralizing antibodies (nAbs) is commonly used to reflect prior SARS-CoV-2 infection. After infection or vaccination, these nAbs remain stable for a minimum of three months, with some antibody levels persisting for as much as eight to fifteen months after the initial antibody response.

The circulation of Bmem has also been used to evaluate the trajectory of COVID-19. Early in SARS-CoV-2 infection, Bmem typically expresses immunoglobulin M (IgM) and subsequently shifts towards CD21 expression.

For as much as 11 months after infection, Bmem will switch to IgG at increasing levels. Moreover, CD27+ and CD71- Bmem levels may remain stable for greater than 12 months following infection, thus indicating a durable B-cell memory response. 

Various SARS-CoV-2-specific T-cells have been characterised, including CD8+ and CD4+ effector and memory subsets, in addition to T helper cells (Tfh). Each CD4+ T-cell and Tfh cell responses remain robust for about one month following infection, whereas CD8+ T-cells remain detectable in 70-80% of convalescent samples presently point.

These T-cell responses can remain detectable as much as eight months post-infection. Nonetheless, unlike Bmem, Tmem levels typically decline over time.

Immune response to vaccination

Adenoviral vector and messenger ribonucleic acid (mRNA) COVID-19 vaccines rapidly developed following the onset of the pandemic and subsequently received approval in many countries worldwide. These two sorts of COVID-19 vaccines were designed to provide each humoral and cellular responses against the SARS-CoV-2 spike protein.

High levels of nAbs have been detected 4 weeks following administration of each adenoviral and mRNA vaccines, with convalescent individuals producing much higher antibody levels as in comparison with naïve individuals following vaccination. Plasma cells produced following mRNA vaccination have been detected for as much as seven months.

In comparison with mRNA vaccines, adenoviral vaccines generate significantly lower IgG and nAbs. Antibody levels appear to peak 15-20 days following mRNA vaccination, followed by a decline in nAb levels.

SARS-CoV-2 spike-specific Bmem generated following one mRNA vaccine dose peak one month after receipt of the second vaccine dose. Interestingly, convalescent individuals generate higher Bmem levels in response to the primary mRNA vaccine dose as in comparison with naive individuals because of pre-existing infection-induced immune memory cells. Nevertheless, infection-naïve individuals produce spike-specific Bmem which are detectable for as much as six months after the second mRNA vaccine dose.

Spike-specific CD4+ and CD8+ T-cells also appear to peak throughout the first 4 weeks following completing a two-dose mRNA vaccine series. Nonetheless, in comparison with the stable Bmem levels reported following vaccination, CD4+ and CD8+ T-cell levels appear to say no three months following vaccination.

Immunity against SARS-CoV-2 VOCs 

Several SARS-CoV-2 variants of concern (VOCs) have been reported which are more infective, more prone to cause severe disease, and able to evading vaccine-induced immunity. 

To handle the decreased protection conferred by vaccination against these VOCs, a 3rd booster dose three to 6 months after primary vaccination has been really useful in several countries. As well as, booster vaccination has been shown to reactive Bmem, thus increasing the production of nAbs to bind to and neutralize SARS-CoV-2 VOCs.

Conclusions 

The robust efforts to know immune memory elicited after COVID-19 vaccination and/or SARS-CoV-2 infection, and the sturdiness of those responses will assist in designing future therapies to treat vulnerable individuals. Clinical assays able to identifying Tmem and Bmem will allow researchers to evaluate vaccine efficacy to find out the necessity and timings for subsequent booster doses.

Further research is required to find out the capability of immune memory in recognizing VOCs and providing protection from infection or severe COVID-19 and associated fatality. Taken together, these efforts will aid in combatting the continued COVID-19 pandemic.

Journal reference:

• Hartley, G., Edwards, E., O’Hehir, R., et al. (2022). Latest insights into human immune memory from SARS‐CoV‐2 infection and vaccination. Allergy. doi:10.1111/all.15502.