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Pandemic at a perspective: What comes next

Author: Himanshu Sadulwad

Prevention of any disease is largely based on the epidemiology of the disease. To effectively lower the number of COVID-19 cases globally, special emphasis has been placed on these epidemiological studies which help us to find the underlying causes of the surge in cases.

Variants of Concern

Like other viruses, COVID-19 does evolve over time. Most mutations in the SARS-CoV-2 genome have negligible impact on viral functions. But some variants have gained attention due to their rapid emergence, transmission and clinical implications. These are termed as variants of concern.

Early in the pandemic, a study which monitored amino acid changes in the spike protein of SARS-CoV-2 identified a D614G (glycine for aspartic acid) substitution that became the dominant polymorphism globally over time. In animal and in vitro studies, viruses bearing the G614 polymorphism demonstrate higher levels of infectious virus in the respiratory tract, enhanced binding to ACE-2, and increased replication and transmissibility compared with the D614 polymorphism. The G614 variant does not appear to be associated with a higher risk of hospitalization or to impact anti-spike antibody binding. It is now present in most circulating SARS-CoV-2 lineages.

Alpha (B.1.1.7 lineage)

This variant was first reported in the UK in December 2020. It became the globally dominant variant until the emergence of the Delta variant. This variant includes 17 mutations in its viral genome. 8 of these are in spike proteins. This results in an increased affinity of the protein to ACE 2 receptors which enhances the viral attachment and subsequent entry into host cells. This variant was reported to be 43% to 82% more transmissible than the preexisting variants. It was also associated with an increased in mortality compared to other variants.

Beta (B.1.315 lineage)

The Beta variant was first identified in South Africa in October 2020. It includes 9 mutations in the spike proteins out of which 3 increase the binding to ACE receptors. The main concern with this variant was immune evasion as it had reduced neutralization by monoclonal antibody therapy, convalescent sera and post-vaccination sera.

Gamma (P.1 lineage)

The third variant of concern was identified in December 2020 in Brazil. It harbors 10 mutations in the spike proteins. It did not become a globally dominant variant.

Delta (B.1.617.2 lineage)

This variant was initially identified in December 2020 in India and was responsible for the deadly second wave of COVID-19 infections in April 2021. It harbors 10 mutations in its spike proteins. Compared to the Alpha variant, the Delta variant was more transmissible and associated with a higher risk of severe disease and hospitalization.

Omicron (B.1.1.529 lineage)

This variant was first identified by the WHO in South Africa on 23 November 2021 after a sharp rise in the number of COVID-19 cases. It was quickly recognized as a VOC due to more than 30 changes to the spike protein of the virus. Initial modeling suggests that it shows a 13-fold increase in viral infectivity and is 2.8 times more infectious than the Delta variant. It is also reported to evade infection and vaccine induced humoral immunity to a greater extent than prior variants.

Immune evasion

Omicron appears to escape humoral immunity and to be associated with a higher risk of reinfection in individuals previously infected with a different strain. These observations are further supported by findings from several laboratories, in which sera from individuals with prior infection or prior vaccination did not neutralize Omicron as well as other variants; in some cases, neutralizing activity against Omicron was undetectable in convalescent as well as post-vaccination sera.

Severity of disease

Observational data suggest that the risk of severe disease with Omicron infection is lower than with other variants. An analysis from England estimated that the risk of hospital admission or death with Omicron was approximately one-third that with Delta, adjusted for age, sex, vaccination status, and prior infection. The reduced risk for severe disease may reflect partial protection conferred by prior infection or vaccination. However, animal studies that show lower viral levels in lung tissue and milder clinical features (eg, less weight loss) with Omicron compared with other variants provide further support that Omicron infection may be intrinsically less severe. On the other hand, even if the individual risk for severe disease with Omicron is lower than with prior variants, the high number of associated cases can still result in high numbers of hospitalizations and excess burden on the health care system.

Omicron Sublineages

The original Omicron variant is sublineage BA.1. Sublineage BA.2, which differs by approximately 40 mutations, demonstrates a replication advantage compared with BA.1 and accounts for the majority of Omicron sequences globally. Vaccine efficacy appears largely similar for BA.2 in comparison to BA.1. Although reinfections with BA.2 in individuals with prior BA.1 infection occur, they have been rare and mainly in unvaccinated individuals. Accordingly, BA.1 infection in vaccinated individuals appears to elicit neutralizing antibodies that have potent activity against BA.2 as well.

Other variants within the Omicron lineage include recombinant variants (eg, XE, which is a combination of BA.1 and BA.2) and new sublineages (eg, BA.2.12.1, BA.4, BA.5). Some of these appear to have a replication advantage compared with other Omicron sublineages; however it is unknown whether their impact on disease severity or immune escape differs from that of other Omicron sublineages.

Variants of Interest

VOIs are defined as variants with specific genetic markers that have been associated with changes that may cause enhanced transmissibility or virulence, reduction in neutralization by antibodies obtained through natural infection or vaccination, the ability to evade detection, or a decrease in the effectiveness of therapeutics or vaccination. So far since the beginning of the pandemic, the WHO has described eight variants of interest (VOIs), namely

Epsilon (B.1.427 and B.1.429)

Zeta (P.2)


Theta (P.3)




Mu (B.1.621).


Since the first cases of COVID-19 were reported in Wuhan, Hubei Province, China, in December 2019 and the subsequent declaration of COVID-19 as a global pandemic by the WHO in March 2020, this highly contagious infectious disease has spread to 223 countries with more than 281 million cases, and more than 5.4 million deaths reported globally. This reported case counts underestimate the burden of COVID-19, as only a fraction of acute infections are diagnosed and reported. Seroprevalence surveys in the United States and Europe have suggested that after accounting for potential false positives or negatives, the rate of prior exposure to SARS-CoV-2, as reflected by seropositivity, exceeds the incidence of reported cases by approximately 10-fold or more.

Persons of all ages are at risk for infection and severe disease. However, patients aged ≥60 years and patients with underlying medical comorbidities such as obesity, cardiovascular disease, chronic kidney disease, diabetes, chronic lung disease, smoking, cancer, solid organ or hematopoietic stem cell transplant patients are at an increased risk of developing severe COVID-19 infection. In fact, the percentage of COVID-19 patients requiring hospitalization was six times higher in those with preexisting medical conditions than those without medical conditions. Notably, the percentage of patients who succumbed to this viral illness was 12 times higher in those with preexisting medical conditions than those without medical conditions.

Data regarding the gender-based differences in COVID-19 suggests that male patients are at risk of developing severe illness and increased mortality due to COVID-19 compared to female patients. Similarly, the severity of infection and mortality related to COVID-19 differs between different ethnic groups.

Will it ever end?

Since December 2019, this virus has been wreaking havoc around the globe disrupting all walks of life. While our healthcare systems work tirelessly to provide treatment, researchers have stepped up to help solve the situation.

Although IHME models suggest that global daily SARS-CoV-2 infections have increased by more than 30 times from the end of November, 2021 to Jan 17, 2022, reported COVID-19 cases in this period have only increased by six times because the proportion of cases that are asymptomatic or mild has increased compared with previous SARS-CoV-2 variants, the global infection-detection rate has declined globally from 20% to 5%.

Despite the reduced disease severity per infection, the massive wave of omicron infections means that hospital admissions are increasing in many countries and will rise to twice or more the number of COVID-19 hospital admissions of past surges in some countries according to the IHME models.

So the question stands, when will this be over?

Pandemics do not end overnight with a parade or some armistice. Usually, the virus evolves to a less severe variety, the majority of the population develop resistance to it and the disease fades into the background. If this happens the era of extraordinary measures by governments to control the transmission of the disease will be over. The pandemic may end but COVID-19 will return.


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(This is the third article in the series, Pandemic at a perspective)

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