The Passing Pandemic? Perspective and Projections for COVID-19

The Pandemic and Realms of Human Life

COVID-19 as a disease and SARS-CoV-2 as its causative organism, continue to remain an enigma [1]. While we continue to explore the agent factors, disease transmission dynamics, pathogenesis, clinical spectrum of the disease and therapeutic modalities, the grievous nature of the disease is persisting and evolving further in various regions around the world. Simultaneously, it is apparent that the virus SARS-CoV-2, is here to stay for the foreseeable future [2]. The future of the disease, of course, appears to depend on various known and unknown factors including the effects of seasonality on the disease transmission and spread, the evolving viral mutations and variants, certain genetic factors, level and duration of effective immune response to the disease, the availability of COVID-19 vaccines, and the lifestyle choices made by individuals and measures enforced by the governments. It is hard to imagine a worse pandemic than COVID-19 which has affected not only health but every realm of human life, being the most disruptive pandemic in modern times. In fact, the pandemic seems like a singular, once-in-a-lifetime event. Further, the pandemic is ongoing with no definite end in sight, and there are serious challenges posed by SARS-CoV-2 virus and COVID-19 as the disease to humanity.

Research, Rationality and Mass Hysteria

Fundamentally, the viruses outnumber all the members of animal and plant kingdom, including bacteria. The public-health measures against an epidemic are age-old and general rather than specific. Many are based on the human experience with the Spanish Flu pandemic of 1918. Initially, at the start of the COVID-19 pandemic they aimed at stemming the tide of the novel virus and have been applied in certain modified forms like avoiding close and non-ventilated spaces. It needs to be stressed that the COVID-19 is not the deadliest pandemic, the HIV infection carries the dubious distinction of having killed more people than died during the COVID-19 pandemic. As now established, COVID-19 is not just result of the infection due to the SARS-CoV-2 virus. The immune response to the virus largely determines the disease course [3].The patients with severe forms of the disease have an increased likelihood of IgG1 antibodies with fucosylated Fc glycans leading to enhanced interaction and binding with the immune- activating Fcγ receptors (FcγRs) on immune effector cells [4]. The latter results in increased production of cytokines like interleukin-6 and TNF by monocytes and its attendant clinical manifestations [5]. Added to this, some of the variants are associated with a higher viral load, and potentially with increased transmissibility, and propensity to cause more severe disease or worse outcomes. There is a chance that vaccines currently being administered may not provide sufficient immunity against new emerging variants. Also, the therapeutic choices in case of moderate to severe disease are limited and unsatisfactory. Thus, COVID-19 has had a major impact on human health globally; infecting a large number of people, causing severe disease resulting in morbidity and excess mortality, especially among older and vulnerable populations, having a negative impact on physical and mental health and associated long-term health sequelae. It has interrupted routine healthcare services and led to disruptions to travel, trade, education, and other socio-economic activities. This is further complicated by the mass hysteria generated, accentuated, and propelled largely by the electronic media.

The Mutagenesis and Emerging Variants

The understanding of the nucleotide variations in the SARS-CoV-2 genome provides a useful insight for the evolution of the disease and the propagation of the pandemic [6]. Whereas most mutations and variations have no impact on the viral ability to transmit or disease severity, some mutations have a significant impact on transmissibility, infectivity, or lethality. Thus, the mutations and variants may have far-reaching consequences for future trends. Some of these mutations have possibly arisen as a result of the virus evolving under immune selection pressure in infected individuals, especially in patients with mild rather than those with severe disease. The variants arise as a result of natural selection to facilitate the spread of viral infection. As such, the SARS-CoV-2 virus has a low mutation rate by virtue of the nsp14 protein acting as a 3′-5′ exoribonuclease on both the single-stranded and double-stranded RNA during the viral replication cycle [7].

Further, SARS-CoV-2 can resort to RNA viral evolution through recombination (synthesis of chimeric RNA molecules from two different progeny genomes) and reassortment (the packaging within a single virion of genomic segments from different progeny viruses. The SARS-CoV-2 has a steady rate of mutations, and the mutations may accumulate over time. The evolving variants affect the transmissibility, disease severity, resultant immunity, which in turn, have either replaced the previous ones or de-escalated depending on these properties. The variants have been categorized using WHO label, lineage and presence of the spike and other mutations, and their properties concerning, transmissibility, immune response, and infection or disease severity. The variants pose a challenge for preventive measures including the vaccination, as a number of variants are associated with immune escape, and therapeutics, as the response of the variants to therapeutic agents may differ.

The SARS-CoV-2 variants, in general, maybe grouped as Variants of concern (VOCs), Variants of Interest (VOIs), Variants under monitoring (VUMs) and De-escalated variants. Though, it is possible for a VOC, VOI, or VUM to also be a part of a broader VOC, VOI, or VUM definition, and belong to more than one group. Presently, the newly emerged variants, Omicron and its subvariant, BA.2, are of heightened importance. Currently as updated, the Variants of Concern (VOC) include Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and the new-comer, Omicron (B.1.1.529). Whereas the Alpha, Beta, Gamma, and Delta variants are associated with increased transmissibility and disease severity, the Omicron has increased transmissibility and reduced disease severity [8]. The Variants of Interest (VOI) comprise of Mu (B.1.621), Lambda (C.37), and unlabelled (AY.4.2). Whereas Variants under monitoring (VUM) include linages and mutations, such as, B.1.1.318, B.1.617.2 + K417N, C.1.2, B.1.617.2 + E484X (d), B.1.617.2 + Q613H, B.1.617.2 + Q677H, and B.1.640.The current SARS-CoV-2 variants of importance are D614G (B.1), Alpha (B.1.1.7 and B.1.1.7+E484K), Gamma (P.1), Delta (B.1.617.2), Omicron -BA.1 (B.1.1.529), and Omicron BA.2 (Table 1).

In addition, there is a class of De-escalated variants, which comprises of additional variants, which have been de- escalated as the variants are no longer circulating or existing for a long time without impact on the pandemic situation, or variants are circulating but not associated with concerning epidemiological properties [9]. As updated recently, the de- escalated variants now include Epsilon, Eta (B.1.525), Theta (P3), Kappa (B.1.617.1), B.1.620, P.2, P.3, and others like A.27, A.28, C.16, and B.1.214.2.

Omicron: Priming for Immunity or Disaster

The newly emerged SARS-CoV-2 variant, Omicron (B.1.1.529), first reported from South Africa and Botswana during November 2021, appears to have increased transmissibility with reduced disease severity [10]. In addition, it generates a potent immunity. Phylogenetically, it contains many more mutations than any previous VOCs. It carries a total of 47 mutations in its genome, including 26 mutations in the spike (S) gene, and 13 mutations in the receptor-binding domain (RBD) in the S gene [11]. It has been documented that, the Omicron variant has increased transmissibility and enhanced viral binding affinity. In addition, due to the presence of five novel mutations adjacent to the ACE2 and antibody binding sites, it may harbour an immune escape property and manifest striking antibody evasion [12]. The in vitro neutralization assay shows that the mean neutralization titters by sera from convalescent COVID-19 patients are significantly reduced against the Omicron variant than other variants [13]. The current researches, as well as clinical findings related to the Omicron variant, have led to a rampant view, both among medical professionals and the public that the illness due to Omicron is likely to be a mild one and might help to develop immunity to protect against a more severe variant in the future. The sub-variant BA.2, spreading in various geographical regions also appears to cause a less severe clinical disease [14]. The sub-variant appears to be even more transmissible than the Omicron variant as its transmission is reportedly higher among household contacts of BA.2 cases (13.4%) as compared to 10.3% for the Omicron cases [15]. The sub-variant of Omicron, BA. 2, which shares many of the mutations in Omicron, has further 28 mutations, not present in the Omicron variant including those in the spike protein. While the original BA.1 variant is relatively easy to track due to a spike deletion (H69/V70), the BA.2 does not contain this mutation hence not simple to detect by PCR testing. Instead, its monitoring requires additional genomic sequencing. Due to its evasiveness, some researchers have dubbed the BA. 2 as the ‘stealth omicron’ [16]. The WHO is yet to categorize BA.2 as a ‘Variant of concern’. The current vaccines appear to offer the same level of protection against symptomatic disease both due to Omicron as well as its sub-variant BA.2. But, due to the relatively small number of confirmed cases of Omicron’s sub-Variant BA.2, the conclusions are provisional. There is lingering fear among the researchers that perchance the Omicron and its sub-variant, BA.2 may be priming the immune response for a disaster due to future SARS-CoV-2 variants.

The Preventive Measures and Therapeutics

With the unprecedented and on-going pandemic, the scientific knowledge had evolved with the research at a fast pace leading to fast development and deployment of the vaccines. They have been developed fast and used under emergency authorization, to tackle the growing pandemic. The downside has been a failure to inspire full public confidence in their efficacy. In addition, people are worried about their long-term effects and complications. There are concerning issues related to exceedingly rare cases of myocarditis, the issues about neurological degenerative disorders, and fertility. There is a glaring fact is that more people have died of COVID-19 since the vaccine was developed than before the vaccine was developed. Further, the data from an array of studies shows that the immunity from the vaccines declines over time, highlighting the need to develop vaccines offering greater protection may be needed to fight off the highly contagious variant. Furthermore, various population groups are weighing freedom to make their own decisions versus the eventuality of mild disease course and symptoms.

On top of these issues, the enforced social isolation as the fallout of the infection is another distasteful and controversial issue. Finally, fear and desperation are giving away to inevitability, among those who feel protected from the virus worst effects because they are vaccinated as well as those who believe that risks of the disease are exaggerated. The empathy of the society toward those vulnerable is vehemently giving way to socio-economic issues like jobs and social and mental strains. These issues dilute the enforcement of preventive measures including masking and vaccination programs. The preventive measures and Vaccines have transformed the pandemic, but there is still a dire need for suitable drugs to treat the disease and its complications. The use of various therapeutic agents has been endorsed and disproven by the RECOVERY Trial (Table 2). These drugs are indicated at different stages of the infection. As per the Recovery Trial results, out of 100 ICU admitted COVID-19 patients on ventilators for 28 days, 60 patients were already likely to recover, 12 pts survived because of the drug therapy, whereas 28 still died despite it [17]. The breakthroughs to develop more effective therapeutic modalities are, still, required to improve the disease outcomes.

There is the issue of long-term immune response to the infection and related complications in form of long Covid. For the survivors of the pandemic, the virus can have deleterious health effects that linger on for an indefinite period leading to a range of complications. There are significant short-term as well as projected long-term neurologic manifestations of COVID-19 in patients who have recovered. These involve impaired physical functioning and mobility disorders, and impact on the autonomous nervous system, especially in older patients with mild and moderate disease and warrant further prospective studies. The virus is capable of damaging the cortical structures which control the coordination of movement, such as the basal ganglia, initiating a process of neurodegeneration [18]. The viral infections have been documented to cause long-term neurological complications, as was documented in survivors of the 1918 Spanish Influenza, who were found to have two or three times more likelihood to develop Parkinson’s disease at some point in their life. As early as in the 1990s, antibodies to the coronaviruses were identified in the cerebrospinal fluid of Parkinson’s patients [19]. During the past two years, case studies have been published describing patients who developed acute Parkinsonism abnormalities such as tremors, muscle stiffness, and impaired speech following Covid-19 infection [20]. The disruption of the immune system in these patients may affect variously. There is seen new-onset diabetes or worsening of diabetes in COVID-19 patients [21]. The cardiac complications include myocarditis and cardiomyopathy. In addition, myocarditis and myopericarditis have been associated with COVID-19 vaccination. The Oxford-AstraZeneca vaccine has been linked to very rare cases of clotting disorders. Some recently immunized people have suffered unusual clots, including cerebral sinus vein thrombosis (CSVT). On the other hand, the SARS-CoV-2 infection itself may lead to coagulation disorders. The therapeutic measures to treat the long-term effects and complications need to be explored.