*3.3.1.2 Herd immunity in the context of COVID-19*

Currently there are multiple vaccines approved internationally for human use and immunization campaigns are urging communities to get vaccinated, therefore reducing the number of susceptible in hopes to achieve herd immunity. However, there are multiple factors to consider in achieving herd immunity from the SARS-CoV-2 virus.

Originally, with an estimated BRR of 2–3, researchers estimated the proportion of the population needed to be immunized to induce Herd Immunity around 50–67% [31–33]. Since then, the emergence of new SARS-CoV-2 variants, most famously the Delta variant, studies suggest a higher BRR (>5) [34, 35] than the alpha variant (2–3) [31–33, 36–39] increasing the vaccination/immune threshold needed in order to achieve a protective effect. An increase in the necessary number of individuals vaccinated propose additional hurdles in reaching Herd Immunity, with the ever-increasing anti-vax movement or individuals acting as "freeloaders" (i.e., individuals who are not vaccinated, yet expect to be protected by the rest of the community being vaccinated).

Secondly, future SARS-CoV-2 variants may mutate enough where the protection offered by the currently available vaccines or natural immunity may no longer suffice. The emergence of the Delta variant showed a reduced vaccine effectiveness compared to the previous variants, which the vaccines were developed from [40, 41]. While currently approved vaccines still provide significant protection from the Delta variant for reduced risk of infection and disease severity, the reduction in vaccine effectiveness is alarming. If emerging variants significantly or completely evade the protection offered by current vaccines or natural immunity, individuals may no longer fall under the immune proportion of the population. An example of this possible situation was reported in Manaus, Brazil, where by December 2020 the population was estimated to have naturally achieved the herd immunity threshold (i.e., before vaccinations were approved and available), estimated at 67%, yet experienced a wave of hospitalizations in January 2021 [42]. This case study further highlighted the limitations with calculating Herd Immunity. Possible reasons for the Manaus outbreak were an overestimation of the immune population, a possible waning immune response, mutants capable of evading responses from previous natural infection, and mutants may have higher transmissibility than previously circulating lineages [42]. Future scenarios where Herd Immunity may not be achievable or severely reduced would be staggering in relation to vaccination campaigns and reaching herd immunity—a grave threat to international health security.

## *3.3.2 Artificial immunization/natural infection*

All COVID-19 vaccines authorized or have received emergency use authorization (EUA) by FDA, EU/EEA, or WHO require a two-dose schedule except for the Janssen vaccines. All these vaccines require a period of 21 days to 12 weeks spacing between the primary and secondary dose [43]. In the early phase of the pandemic to reduce widespread community transmission, logistical issues, and shortages, many countries (e.g., UK, Canada) elected to delay the second dose in the population, thereby increasing the number of individuals with at least one dose. Policies such as the aforementioned in conjunction with waning of immunity after SARS-CoV-2 natural infection may result in large groups of people with only partial immunity against SARS-CoV-2 [43].

The Darwinian selection of variants with mutations for immune escape and its transmission in the community will depend on substantial selection pressure [44]. The greatest potential for the emergence of these immune escape mutations will be in those hosts with highest viral loads (increased mutations) while the greatest selection pressure will be in those with strongest immunological response [2, 44]. The level of immunological protection conferred after first dosage is dependent on the type of vaccine product in addition to the individual characteristics and variant [43]. In individuals with poor immunological response after first dose, there is potential for greater infection burden [44]. These individuals will have higher assumed rates of evolutionary adaptation because of higher viral load and replication. In those individuals with strong but partial immunological response, the infection rates would be lower but evolutionary selection pressure would be large, resulting in high rates of viral adaptations. Previous phylogenic research done on influenza viruses suggested the viral evolution and emergence of immune escape variants is maximum in those individuals with partial immunity (i.e., intermediate levels of selection and viral replication) [45]. Thus, having partially immunized individuals could lead to short-term benefits such as reduced peak of disease but in long term can result in higher infection burden and substantially higher risk of viral evolution to immune escape variants [44].

### *3.3.2.1 Chemical and biological therapy*

Several monoclonal antibodies were developed against the spike protein of SARS-CoV-2 to block the transmission of the virus inside the cells [46]. A single (Bamlanivimab) or combination monoclonal antibodies (Bamlanivimab/ Etsevimab or Casirivimab/Imdevimab) received EUA for therapeutic management of SARS-CoV-2 and post-exposure prophylaxis [47, 48]. In theory, administration of monoclonal antibody therapy can alter the immunological selective pressure resulting in viral adaptation for the emergence of variants resistant to one or more monoclonal antibodies [49, 50]. This potential for the emergence of monoclonal antibody resistance has been observed in immunocompromised patients [51–53]. In trials for monoclonal antibodies, mutations resistant to antibodies were detected by

### *Biological Determinants of Emergence of SARS-CoV-2 Variants DOI: http://dx.doi.org/10.5772/intechopen.104758*

next generation sequencing (NGS) assay in 10% of the patients receiving therapy with its transmissibility not determined [54]. Recently, a Wisconsin (WI) study using Bamlanivimab described the emergence of new resistant mutation E484K with further transmission to nearby contacts [55]. The emergence of variants with reduced susceptibility to neutralizing antibodies after polyclonal convalescent plasma therapy provides further proof of the effect of immunological selective pressure on emergence of new variants [49, 56]. It is conceivable, the widespread use of monoclonal or polyclonal antibody therapy may reduce barriers for the emergence of resistant variants to these antibodies which can further transmit to wider communities, potentially becoming a variant of concern. A widespread genomic surveillance is warranted to identify and control the spread of these antibody resistant variants [55].

## *3.3.3 Immunosuppressed individuals*

During evaluation of the efficacy of vaccines, subjects with inhered or acquired immunodeficiencies are excluded from clinical trials. Therefore, there are limited information about the immunogenicity of SARS-CoV-2 vaccines among these patients. Field studies evaluating the effectiveness of COVID-19 vaccines demonstrate that immunocompromised subjects mount a lower antibody response when compared with immunocompetent subjects [57].

Viruses are highly sophisticated molecular machines that can go into an adaptive evolution in the human host establishing a latent reservoir, integrating into the human genome, or causing a chronic infection. Viruses such as hepatitis B virus, hepatitis C virus, and human immunodeficiency virus go into latent stage evading the host immune response while other viruses like Ebola can persist in immune sanctuaries [58]. Considering COVID-19 is an infection of pandemic proportions, it is plausible to think human host immune pressure can contribute to SARS-CoV-2 genetic diversity and selection with phenotypic changes [59]. Consequently, it is necessary to address the relationship between viral persistence in the immunosuppressed host. As a matter of fact, one of the hallmarks of SARS-CoV-2 is its capacity to co-opt various cellular factors and machineries damping the immune response [60]. Although not yet demonstrated, it is plausible to suggest SARS-CoV-2 may establish a latent infection or remain in immune sanctuary. However, SARS-CoV-2 persistence in the immunocompromised patient is well documented [61, 62], with viral persistence reported among cancer patients and transplant recipients [61, 63–67]. Viral coronavirus RNA has been detected up to ~60 days in cancer patients that developed respiratory symptoms. Moreover, the longest persistence of coronavirus RNA is recorded at 151 days in a patient with anti-phospholipid syndrome, which suggest these pathogens are of the opportunistic characteristic [68–70]. In the aforementioned patient, there were 31 substitutions and 3 deletions identified in the genome sequencies from the isolated agent. There were 12 mutations in the spike protein including 7 in the receptor-binding domain segment. Due to severe pulmonary complication the patient died [71]. Increased viral changes were also detected in another immunocompromised patient, whose disease prolonged for 101 days, where viral changes were limited during the first 60 days but increased after receiving plasma form a convalescent patient at days 63 and 65. Moreover, rapid shifts were observed in the spike area during the last days of the monitoring [71]. In another case-series, three patients receiving chimeric antigen receptor (CAR) T cells because of B-cell acute lymphocytic leukemia, showed multiple escape SARS-CoV-2 variants [71]. Consequently, like SARS-CoV-2 longer persistence in immunosuppressed patients, immunosusceptible elderly patients may also harbor the virus for prolonged periods compared to immunocompetent

patients. Gaspar-Rodriguez et al. enunciated in 2021 that SARS-CoV-2 and other coronaviruses potentially establish a long-term, non-productive persistent infection in epithelial, myeloid, and neural host cells until viral clearance is achieved [62]. Prolonged COVID-19 in the immunosuppressed patient can be a determinant of the development of SARS-CoV-2 variants which can be spread among the general population [71]. This persistence of the virus in different types of immunosuppression are listed below.

## *3.3.3.1 SARS-CoV-2 in Cancer patients*

Cancer patients are in immunodepression conditions because of the malignancy and oncological treatments like chemotherapy, radiotherapy, transplants, and immunotherapy. Patients with lung, blood, and bone marrow carcinomas are at a higher risk of harboring the virus for prolonged periods when compared with other cancer patients [72]. Patients with chronic lymphocytic leukemia (CLL) have shown inadequate levels of antibodies as well as cellular immune response [73]. These inadequate immune responses in CLL patients correlates with severe and prolonged forms of COVID-19 and has been supported by late conversion to negative PCR monitoring tests and longer hospitalizations [74]. The impaired humoral and cellular immune response in the CLL patients make these patients long term shedders of SARS-CoV-2 until infection is passed. One case study showed a COVID-19 positive CLL patient having persistent positive PCR test for 105 days after diagnosis [63]. Moreover, during this period a continuous variability in predominant viral variants was observed [63]. This delay in viral clearance in COVID-19 patients has been observed in patients receiving intravenous immunoglobulins as well as in those with hypertension [75].

### *3.3.3.2 SARS-CoV-2 in organ transplant patients*

Organ transplant recipients are patients with long-lasting immunosuppression; therefore, organ transplant recipients have been declared subjects with high risk for severe COVID-19. When COVID-19 positive liver transplant patients were compared with COVID-19 immunocompetent patients, the transplant recipients showed lower prevalence of antibodies against SARS-CoV-2, as well as a faster antibody decline [57]. Regarding viral shedding, immunocompetent asymptomatic COVID-19 infection subjects experience a faster viral clearance when compared with symptomatic individuals [76]. Kidney transplant patients with immunosuppression showed a longer shedding of the virus, of more than 28 days, which was correlated with a prolongation of symptoms [77].

### *3.3.3.3 SARS-CoV-2 in elderly patients*

It is demonstrated SARS-CoV-2 causes highest mortality among elderly populations. Also, viral shedding is increased, enhancing the spread of the virus as it was observed in the increased transmission in nursing homes. An explanation for these complications may be due to the elderly immune system being less competent than in young populations. In the elderly, it appears the production of cytokine and T-cells production worsen the inflammation process especially among those with comorbidities [78]. The increased shedding of SARS-CoV-2 is associated with a more severe clinical presentation and higher viral load peaks [79–81]. The delayed viral clearance in elderly patients' airways can be explained by a decreased respiratory muscle function and diminished mucociliary function [79, 82].

*Biological Determinants of Emergence of SARS-CoV-2 Variants DOI: http://dx.doi.org/10.5772/intechopen.104758*

### *3.3.3.4 SARS-CoV-2 in patients with corticosteroid treatment*

Although corticosteroid therapy is being used to ameliorate the inflammation process, the use of corticosteroids at an early stage can suppress the immune cells which can prolong the clearance of the virus as well as its shedding. In a randomized study in the patients without respiratory failure, the methylprednisolone group showed a median viral shedding of 10 days vs. 6 days in the control group [83].
