SARS-CoV-2-The Role of Natural Immunity: A Narrative Review

Abstract

Background: Both natural immunity and vaccine-induced immunity to COVID-19 may be useful to reduce the mortality/morbidity of this disease, but still a lot of controversy exists.

Aims: This narrative review analyzes the literature regarding these two immunitary processes and more specifically: (a) the duration of natural immunity; (b) cellular immunity; (c) cross-reactivity; (d) the duration of post-vaccination immune protection; (e) the probability of reinfection and its clinical manifestations in the recovered patients; (f) the comparisons between vaccinated and unvaccinated as to the possible reinfections; (g) the role of hybrid immunity; (h) the effectiveness of natural and vaccine-induced immunity against Omicron variant; (i) the comparative incidence of adverse effects after vaccination in recovered individuals vs. COVID-19-naïve subjects.

Material and methods: through multiple search engines we investigated COVID-19 literature related to the aims of the review, published since April 2020 through July 2022, including also the previous articles pertinent to the investigated topics.

Results: nearly 900 studies were collected, and 246 pertinent articles were included. It was highlighted that the vast majority of the individuals after suffering from COVID-19 develop a natural immunity both of cell-mediated and humoral type, which is effective over time and provides protection against both reinfection and serious illness. Vaccine-induced immunity was shown to decay faster than natural immunity. In general, the severity of the symptoms of reinfection is significantly lower than in the primary infection, with a lower degree of hospitalizations (0.06%) and an extremely low mortality.

Conclusions: this extensive narrative review regarding a vast number of articles highlighted the valuable protection induced by the natural immunity after COVID-19, which seems comparable or superior to the one induced by anti-SARS-CoV-2 vaccination. Consequently, vaccination of the unvaccinated COVID-19-recovered subjects may not be indicated. Further research is needed in order to: (a) measure the durability of immunity over time; (b) evaluate both the impacts of Omicron BA.5 on vaccinated and healed subjects and the role of hybrid immunity.

Keywords: COVID-19; Omicron; SARS-CoV-2; cellular immunity; cross-reactivity; hybrid immunity; natural immunity; vaccine-induced immunity.

Figure 1

Natural infection leads to greater production of lgA compared to vaccination. IgA is produced in the mucous membranes through the activation and maturation of B lymphocytes and consequently of plasma cells in subjects naturally infected by SARS-CoV-2. On the other hand, vaccination only minimally elicits the IgA production in the mucous membranes.

Figure 2

T-cell cross reactivity (Heterologous adaptive T cell-mediated immunity). (A). Each colored sphere represents a specific T cell which is directed to a corresponding antigen presented on the MHC. (B). One or more T cell can develop (or it could already exist) a cross-reactivity to other antigens.

Figure 3

Humoral immunity naturally produces memory B cells and antibodies that also recognize viral variants. The long-lived plasma cells in the bone marrow secrete highly selected antibodies, specific and related to the first form selected. They are specific to the encountered pathogen (represented in red) and are against the relative infection. Variant pathogens (e.g., other viruses) can find “holes” in this barrier; however they may encounter a second barrier made up by memory B cells that were less selected. This happens because memory B cells retain a wider range of antigenic affinity and adaptability. Memory B lymphocytes are activated by the different variants; in this case, they either differentiate into long-lived plasma cells or to return to the germinal centers (GCs) in order to replenich the pool of memory B cells.

Figure 4

Self-organized Critically Theory. Each system remains in equilibrium when each trigger is modulated, maintaining homeostasis. In image (A). we see how the humoral and cellular adaptive immune response is perfectly balanced by a not excessive stimulation by an antigen. The result is an optimal and balanced (regulated) response. In image (B). the system undergoes multiple stresses for which it is unable to balance itself, effectively creating an isotype of follicular helper T lymphocytes (DOCK8+, Dedicator of Cytokinesis 8). These lymphocytes give instructions both to the humoral and to the cytotoxic effector compartment, determining the fate of the immune response. In this scenario, the answer is not balanced, but it is rather distorted and leads to an inversion of the adaptive activity, predisposing these lymphocytes to the search of antigens previously encountered, therefore to autoimmunity.