Immunological Memory — The Source of Protective Immunity from a Subsequent Infection

While many successful vaccines act primarily by generating antibodies, there is also a clear need for vaccines that generate populations of highly-specific T cells, especially against infectious agents that successfully escape antibody responses.^[1]

Latest Developments

Based on a latest research, it stated that:^[16]

These results provide further evidence that a three-dose vaccine regimen benefits the induction of optimal functional T cell immune memory.

Table 1. Vaccines do generate populations of highly-specific T cells (Source @erictopol)

Innate Immune System vs Adaptive Immune System

The innate immune system is a conserved defense strategy critical for the initial detection and restriction of pathogens and later activation of the adaptive immune response. Effective activation of innate immunity relies on the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) .

The adaptive immune system, also called acquired immunity, uses specific antigens to strategically mount an immune response. Unlike the innate immune system, which attacks only based on the identification of general threats, the adaptive immunity is activated by exposure to pathogens, and uses an immunological memory to learn about the threat and enhance the immune response accordingly. The adaptive immune response is much slower to respond to threats and infections than the innate immune response, which is primed and ready to fight at all times.

Figure 1.  Steps in adaptive immune process (see [11] for more details)

Note that after monocytes enter the tissue, they become known as macrophages

Antibody-Mediated Immunity (or Humoral Immunity)

Humoral immunity (or is antibody-mediated immunity)

• Involves substances found in the humors (or body fluids)
• The aspect of immunity that is mediated by macromolecules found in extracellular fluids such as:
• Secreted antibodies
• Complement proteins
• Certain antimicrobial peptides
• Contrasts with cell-mediated immunity

Figure 2.  An APC engulfs and digests a foreign bacterium (Source: [15])
An antigen from the bacterium is presented on the cell surface
in conjunction with an MHC II molecule.
Lymphocytes of the adaptive immune response interact with
antigen-embedded MHC II molecules to mature into functional immune cells.

Figure 3.  Antigen presentation stimulates T cells to become 

either "cytotoxic" CD8+ cells or "helper" CD4+ cells 

(Source: Wikipedia)

Immune Memory

Immune memory (or immunological memory), from either primary infection or immunization, is the source of protective immunity from a subsequent infection.^[3-5] Thus, COVID-19 vaccine development is closely tied to the topic of immunological memory.^[6,7]

A thorough understanding of immune memory to SARS-CoV-2 requires evaluation of its various components, including:^[2]

• Antigen Presenting Cells (APCs which includes macrophages, dendritic cells, B cells)
• In the steady state, and when the body is challenged by injury and infection, dendritic cells (one type of APCs)  travel from body surfaces to immune or lymphoid tissues, where they home to regions rich in T cells. There, dendritic cells deliver two types of information: 
• they display antigens, the substances that are recognized by T cells, 
• they alert these lymphocytes to the presence of injury or infection. 
This directs the T cells to make an immune response that is matched to the challenge at hand.
• B Cells (aka B lymphocytes)
• Function in the humoral immunity component of the adaptive immune system by secreting antibodies
• Present antigens and secrete cytokines
• Express B cell receptors (BCRs) on their cell membrane. 
• BCRs allow the B cell to bind to a specific antigen, against which it will initiate an antibody response.
• CD8+ T Cells (aka killer T-cells or cytotoxic T cells)
• Are T lymphocytes that kill cancer cells, cells that are infected (particularly with viruses), or cells that are damaged in other ways
• Most cytotoxic T cells express T-cell receptors (TCRs) that can recognize a specific antigen
• CD4+ T Cells (i.e., T helper cells)
• Help the activity of other immune cells by releasing cytokines, small protein mediators that alter the behavior of target cells that express receptors for those cytokines. 
• Help to polarize the immune response into the appropriate kind depending on the nature of the immunological insult (virus vs. extracellular bacterium vs. intracellular bacterium vs. helminth vs. fungus vs. protist). 
• Are essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils.

as these different cell types may have immune memory kinetics relatively independent of each other. 

A Cross-Sectional Study

Understanding the complexities of immune memory to SARS-CoV-2 is key to gain insights into the likelihood of durability of protective immunity against 

• Re-infection with SARS-CoV-2 
•  2° COVID-19 disease

In the study of Shane Crotty et al,^[2] they assessed immune memory of all three branches of adaptive immunity (CD4+ T cell, CD8+ T cell, and humoral immunity) in a cross-sectional study of 185 recovered COVID-19 cases, extending out to greater than six months post-infection. 

Here are the summary of their results on SARS-CoV-2-specific memory of:

• B cells
• Overall, based on the observations, development of B cell memory to SARS-CoV-2 appeared to be robust and likely long-lasting
• CD8+ T cells 
• The memory CD8+ T cell half-lives (or t_1/2) observed herein were comparable to the 123d t_1/2 observed for memory CD8+ T cells within 1-2 years after yellow fever immunization.^[10]
• Overall, the decay of circulating SARS-CoV-2-specific CD8+ T cell is consistent with what has been reported for another acute virus.

• CD4+ T cells
• Circulating SARS-CoV-2 memory CD4+ T cell responses were quite robust
• 94% of subjects with detectable circulating SARS-CoV-2 memory CD4+ T cells at 1 month PSO
• 89% of subjects with detectable circulating SARS-CoV-2 memory CD4+ T cells at≥ 6 months PSO

Their findings have implications for immunity against 2° COVID-19, and thus the potential future course of the pandemic.^[8,9]

Hybrid Immunity

Based on a new article on Science Magazine, it states that:^[13]

Hybrid vigor can occur when different plant lines are bred together and the hybrid is a much stronger plant. Something similar happens when natural immunity is combined with vaccine-generated immunity, resulting in 25 to 100 times higher antibody responses, driven by memory B cells and CD4+ T cells and broader cross-protection from variants.

Why does this pronounced neutralization breadth occur?  Memory B cells are a primary reason.  They have two major functions:

1. To produce identical antibodies upon reinfection with the same virus
2. To encode a library of antibody mutations, a stock-pile of immunological variants

These diverse memory B cells, created in response to the original infection, appear to be preemptive guesses by the immune system as to what viral variants may emerge in the future.  This brilliant evolutionary strategy is observed clearly for immunity to SARS0CoV-2:

A substantial proportion of memory B cells encode antibodies  that are capable of binding or neutralizing VOCs, and the quality of these memory B cells increase over time.  Thus the increase in variant-neutralizing antibodies after vaccination of previously SARS-CoV-2-infected persons reflects recall of diverse and high-quality memory B cells generated after the original infection.

Also read this companion article on:

How B Cells Adapt?

References

1. Human T Cell Memory: A Dynamic View
2. Immunological memory to SARS-CoV-2 assessed for greater than six months after infection
3. W. A. Orenstein, R. Ahmed, Simply put: Vaccination saves lives. Proc National Acad Sci. 114, 4031–4033 (2017).
4. P. Piot, H. J. Larson, K. L. O’Brien, J. N’kengasong, E. Ng, S. Sow, B. Kampmann, Immunization: vital progress, unfinished agenda. Nature. 575, 119–129 (2019).
5. S. Plotkin, W. Orenstein, P. Offit, Plotkin’s vaccines, 7th edition (Elsevier, 2018), Elsevier.
6. D. S. Stephens, M. J. McElrath, COVID-19 and the Path to Immunity. Jama. 324 (2020), doi:10.1001/jama.2020.16656.
7. F. Krammer, SARS-CoV-2 vaccines in development. Nature, 1–16 (2020).
8. S. M. Kissler, C. Tedijanto, E. Goldstein, Y. H. Grad, M. Lipsitch, Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science. 368, 860–868 (2020).
9. C. M. Saad-Roy, C. E. Wagner, R. E. Baker, S. E. Morris, J. Farrar, A. L. Graham, S. A. Levin, M. J. Mina, C. J. E. Metcalf, B. T. Grenfell, Immune life history, vaccination, and the dynamics of SARS-CoV-2 over the next 5 years. Science, eabd7343 (2020).
10. R. S. Akondy, M. Fitch, S. Edupuganti, S. Yang, H. T. Kissick, K. W. Li, B. A. Youngblood, H. A. Abdelsamed, D. J. McGuire, K. W. Cohen, G. Alexe, S. Nagar, M. M. McCausland, S. Gupta, P. Tata, W. N. Haining, M. J. McElrath, D. Zhang, B. Hu, W. J. Greenleaf, J. J. Goronzy, M. J. Mulligan, M. Hellerstein, R. Ahmed, Origin and differentiation of human memory CD8 T cells after vaccination. Nature. 552, 362–367 (2017).
11. Vaccine bootcamp (nice animation)
12. Human Coronavirus: Host-Pathogen Interaction
13. Hybrid Immunity
14. Understanding the Basics of Memory B Cells—The Antibody Factory
15. Antigen-Presenting Cells
16. Resilient T cell responses to B.1.1.529 (Omicron) SARS-CoV-2 variant