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Change is the law of nature, and SARS-CoV-2 is no exception. Since January 2020, WHO has been monitoring and analyzing the evolution of SARS-CoV-2. Variants are classified as Variants of Interest (VOI) and Variants of Concern (VOC) depending on virulence and transmissibility. The most prevalent are Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1) and the infamous Delta (B.1.617.2). Furthermore, Variants Under Monitoring (VUM) have been recognized which are suspected to affect virus’s characteristics with an indication of posing a future risk. With changes in the variants’ properties, sky rocketing numbers of COVID positive cases along with the boom in vaccination, adaptive immunity is now of global interest. Adaptive immune response or immunological memory is imperative for clearing the viral load off the body as well as protection against re-infection. These responses however differ for natural immunity through infection and vaccine generated immunity. Cluster of differentiation is represented here as a CD. These are further elucidated as CD4 (cluster of differentiation 4) which is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). and CD8+ T cells (often called cytotoxic T lymphocytes, or CTLs) as they are very important for immune defence against intracellular pathogens, including viruses and bacteria, and for tumour surveillance. In general, several factors contribute to the body’s overall immune response, such as cellular system (B cells, T cells, CD4+ T cells, CD8+ T cells, macrophages etc.), physical barriers, environmental influences like immuno-compromising medications, co-morbidities, age, and most importantly infection with an immune escape viral variant, particularly a variation in the spike protein.

There have been common concerns all over the world regarding the same (i) how long does immunological protection last after being infected with SARS-CoV-2? (ii) would new variants pose a chance of re-infection? (iii) how long does the protective effect of vaccination last? (iv) does a recovered person need vaccination?    

In spite of the memory cells and neutralizing Ab responses, there have been cases of SARS-CoV-2 reinfection. Whether these were due to a different strain or waning immunity remains questionable.

Immunity status post natural infection

Post COVID-19 infection, levels of immunity vary between 93% and 100% over 7-8 months in areas where VOCs were widespread. An immunological memory cell study was conducted in a recent research of Dan et al., 2021 where 254 samples were taken from 188 COVID-19 cases, including 43 samples at 6-8 months after infection. Over a period of 8 months, antibodies (Abs) against SARS-CoV-2 spike and receptor-binding domain (RBD) declined moderately over 8 months. There was a significant increase in the memory B-cells against SARS-CoV-2 spike between 1 month and 8 months after infection. However, memory CD8+ T cells and memory CD4+ T cells gradually decreased in 6 to 8 months. Among the antibodies response during the same time period, spike Immunoglobulin G (IgG), Receptor Binding Domain (RBD) IgG, and neutralizing Ab titers declined, while spike IgA was consistently present. The memory B-cells responded variably. Large titers of IgG were detected, minimum quantity of IgA memory B-cells, and a short-lived population of IgM memory B-cells. Large majority of memory CD8+ T cells and memory CD4+ T cells were detected a month after infection. While the population of CD8+ T cells decreased by ~50% at the end of the 6-8 months period,  CD4+ T cells remained high (~93%) by 6-8 months. SARS-CoV-2 spike-specific memory CD4+ TH cells with the specialized capacity to help B-cells produce Abs were also active.

In spite of the memory cells and neutralizing Ab responses, there have been cases of SARS-CoV-2 reinfection. Whether these were due to a different strain or waning immunity remains questionable. It is clear, though, that encounter with a variable spike protein reduces the potency of engendered Abs, suggesting diminished but not abolished immunity due to changes in neutralizing Ab epitopes in spike. 

Immunity status post vaccination

In fact, the specific epitopic region of the spike proteins is the basis for development of all currently licensed vaccines, as it is the target for neutralizing Abs. These vaccines have demonstrated induction of Ab levels of similar or higher magnitude as compared to convalescent individuals. 

Mutations in key neutralizing Ab spike epitopes which benefit the virus to evade Ab recognition, can be a threat for vaccine efficacy. This was observed when vaccines based on the original Wuhan SARS-CoV-2 spike, proved less effective against the rapidly spreading delta variant. Exceptions where effective blocking of infection was observed was reasoned to higher magnitude of Ab titers. Even if some classes of Abs lose reactivity, the overall anti-S Ab response, including the RBD, is polyclonal and consists of Abs that also recognize the VOCs.  However, in some cases, infection with the delta variant was effectively blocked, which was due to higher magnitude of Ab titers. Although there is loss of reactivity of some classes of Abs, there is a substantial polyclonal response of anti-spike Ab and the RBD, which helps the Abs to recognize VOCs. 

As for SARS-CoV-2 and other infections, vaccine-induced Abs weaken with time. However, owing to the memory B-cells which rapidly clone and differentiate into Ab-secreting plasma cells upon re-exposure, mRNA vaccine induced Abs were detected more than 6 months after vaccination.

As an evolving strategy, SARS-CoV-2 changes its spike proteins to enable survival in new hosts, and so does our immune system. Diversity of memory B-cells could be the survival instinct of the immune system, ready to combat the various viral variants, which may emerge in the future.

Immunity status post infection and vaccination

Immune response is magnified in individuals who after recovering from COVID-19, acquire natural immunity and a further boost with vaccination. This amalgam of immunities is termed as Hybrid Vigor Immunity or simply, “Hybrid Immunity” as described by research paper of Crotty 2021. Because of the robustness of hybrid immunity, some scientists are using the term “Superhuman Immunity” or “Bulletproof Immunity”.

Physiologically, both B cell and T cell components contribute to hybrid immunity. Studies demonstrated robust neutralizing Ab responses against natural infection with beta and the ancestral Wuhan strain. In addition, vaccination of individuals previously infected with non-beta SARS-CoV-2 demonstrated neutralizing Abs against beta. These unanticipated immune responses were ~100 times higher than infection alone and 25 times higher than after vaccination alone – even though neither the vaccine nor the infection involved the beta spike protein. 

This pronounced neutralizing breadth occurs because of memory B-cells. As is known, the major function of memory B cells is to produce identical Abs upon reinfection with the same virus. Another very important function is to encode a library of Ab mutations. As an evolving strategy, SARS-CoV-2 changes its spike proteins to enable survival in new hosts, and so does our immune system. Diversity of memory B-cells could be the survival instinct of the immune system, ready to combat the various viral variants, which may emerge in the future. This works by neutralizing VOCs through production of a large population of Abs by memory B cells. After one episode of Ab mass production, the quality and scope of these memory B cells increases. Therefore, memory B cells generated after infection, plus those generated after vaccination, cumulate their experiences to generate a diverse and much stronger immune response. 

Another explanation for the development of Superhuman Immunity is that it gets the best of both worlds. SARS-CoV-2 possesses 25 different viral proteins, generating natural immunity against non-spike proteins.

Another player in the immunological memory game are the T cells. TH/ CD4+ T cells instruct germinal centers, which are the B-cell activation zones, to generate diverse B cells in response to infection or vaccination. Moreover, memory B cells are quiescent cells and upon stimulus, TH cells drive them to produce Abs specific to the viral variant. Studies have in fact demonstrated a 5-10 fold increase in memory B cells, and a fairly high magnitude of Ab titers during hybrid immunity as compared to natural or vaccine generated. 

T cells are imperative for immunological memory as most T cell epitopes are not mutated in VOCs, thus contributing to enhanced breadth of the immune response. Broadly, natural as well as vaccine-generated immunity weakens the neutralizing Ab activity against most VOCs. This could be due to selection pressure of SARS-CoV-2 which constantly mutates to survive and evade immunities. 

Another explanation for the development of Superhuman Immunity is that it gets the best of both worlds. SARS-CoV-2 possesses 25 different viral proteins, generating natural immunity against non-spike proteins. On the other hand, most of the COVID-19 vaccines consist of a single antigen, spike, generating spike-specific immunity after vaccination. Thus, when both immune responses synergize, memory T cells, CD4+ T cells and CD8+ T cells produce a heightened response.  

Overall, hybrid immunity to SARS-CoV-2 substantially enhances the immune response and confers strong resistance against VOCs and possibly VUMs. This phenomenon is in fact being viewed as light at the end of the dark tunnel. Speculations are that development of hybrid immunity, along with massive vaccination drives around the world could put an end to, or at least halt the COVID-19 pandemic for a significant amount of time. If nature is kind or we are able to further scientific developments, we might just encounter SARS-CoV-2 as seasonal flu and lives will return to “Normal” as the pre-pandemic-era. 

Composed by: “Dr. Geetika Ahuja is a cereal carbohydrate specialist with R&D experience in genetic and biochemical alterations in cereal grain digestibility and its nutritional implications. She has been awarded with several prestigious international awards and scholarships; has won accolades at Life & Health Science Conferences; and has various international publications to her credit. She has contributed as Research Associate in the Biothreat Mitigation Project at CBRN Defence, DRDO; and is currently a Senior Scientific Consultant at Gel Kraft Healthcare Pvt Ltd.”

Photo by Unsplash

InnoHEALTH magazine digital team

Author InnoHEALTH magazine digital team

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