New variants of the SARS-CoV-2 virus continually emerge and pose a challenge to pandemic control through vaccination. Which variants are of concern and why.
What are the coronavirus variants
The coronavirus SARS-CoV-2 is the infectious agent responsible for Covid-19, a disease characterized by hyperinflammation, respiratory impairment, and other pathological changes that occur primarily in infected elderly persons and frail persons, i.e., persons with multiple co-morbidities.
A new viral variant is characterized by one or more mutations in the virus sequence that differentiate it from other circulating variants. New variants of SARS-CoV-2 continually emerge and raise widespread concerns about their infectivity, virulence, and ability to escape immunity induced by currently available vaccines.
Multiple variants of SARS-CoV-2 have been documented worldwide during this pandemic. By comparing the genetic differences of the various viral variants, it is possible to reconstruct a phylogenetic tree and understand how the various variants are related to each other.
To understand which variants are of concern, and why, it is necessary to conduct a series of studies on the SARS-CoV-2 virus genome, on the changes in structure of viral antigens caused by the new variants, and on the interaction between variant-modified antigens and vaccine-induced antibodies.
We must remember that vaccines approved in Western countries are based on the viral spike protein as antigen. Therefore, viral variants that modify the composition and structure of the spike protein, in the part recognized by the antibodies induced by the available vaccines, are of particular interest and may cause concern for the so-called immunological leakage.
Variants of interest (VOI)
Variants of interest are defined as those that are associated with changes in the binding capacity of the virus to its receptor on human cells, or associated with reduced neutralization by antibodies generated against the previous infection or by vaccination, or with an increase in the transmissibility or severity of the associated disease. For a variant to be classified as a variant of interest, there must be evidence of an association with an increasing proportion of cases, or with outbreaks of infection.
Variants of concern (VOC)
A variant of interest is then referred to as a "variant of concern" (VOC) if there is evidence of its impact on diagnosis, severity of induced disease, spread, or possible resistance to immunity conferred by vaccination.
Specifically, when there is evidence:
• increased transmissibility
• an increase in the severity of the disease induced by the infection
• a decrease in the ability of antibodies generated during a previous infection or by vaccination to neutralize it
• of reduced protection conferred by vaccination for severe disease.
Origin and fate of variants
Variants arise, spread to outbreaks and populations, and then disappear, being replaced by other variants characterized by a greater capacity for infectivity and ability to spread in the population. This is what happened in the early months of the pandemic, when the G614 variant replaced the original D614 variant worldwide.
The fate of a new variant is generally determined by natural selection. Mutations that confer a competitive advantage over virus infectivity or escape from innate or induced immunity tend to spread through the population, increasing their prevalence, whereas those that reduce the virus' ability to infect the host tend to disappear from circulation.
Alpha variant (B.1.1.7)
The Alpha variant was first detected in the United Kingdom and designated as a VOC in December 2020.
Since then, Alpha has been detected in nearly 200 locations worldwide. It contains several key mutations in the spike protein that distinguish it from the original Wuhan strain. One of these mutations is N501Y, which is thought to enhance viral replication. It also features another mutation, P681H, whose biological function is unclear. Alpha is estimated to be about 50% more transmissible than the original Wuhan strain, although studies show considerable variation in the magnitude of this estimate. Data on association between Alpha and disease severity are conflicting. Existing vaccines and monoclonal antibody
treatments have been effective against Alpha.
Delta variant (B.1.617.2)
The Delta variant, which contains several characteristic mutations, was first identified in India. It spreads more easily than previous variants, and the Delta variant has been estimated to be twice as contagious as the original SARS-CoV-2 strain from Wuhan, and about 40-60% more transmissible than Alpha; Delta has in fact replaced all other variants almost completely, in all countries. Clinical studies have indicated that the Delta variant is associated, on average, with more severe disease than that caused by the earlier
variants. In experimental models, such as Syrian hamsters, the Delta variant showed a more prolonged period of persistence in the lung, compared with the original virus variant, and induced moderate or severe lung disease in 40% of infected animals. All FDA-approved or licensed vaccines have been effective in preventing severe disease in individuals infected with the Delta variant, and in reducing the risk of hospitalization and death. Delta variant is amenable to treatment with FDA-approved monoclonal antibodies.
The Omicron variants
The Omicron variant was first identified in South Africa. It is characterized by a substantial number of mutations, including 36 mutations in the sequence encoding the spike protein. Omicron is more diffusible than the other variants, including Delta, and is replacing the Delta variant in most parts of the world.
Regarding its pathogenicity, evidence is emerging indicating that the Omicron variant causes milder symptoms than earlier variants. Among other things, the "decoupling" between the sharp increase in the number of infections and the mortality rate, which has remained low and stable, has become evident, first in South Africa and then in other countries. Indeed, while the number of swab-positive cases has risen to record levels in many countries, hospitalization and mortality rates are lower than in other phases of the
pandemic, when the number of cases was lower. Early evidence suggests that fully vaccinated people who become infected with the Omicron variant may spread the coronavirus to others. However, those vaccinated are protected from the risk of hospitalization, serious illness, and death. Many monoclonal antibodies appear to be ineffective against Omicron infection.
The two SARS-CoV-2 variants, BA.4 and BA.5, share the same structure and mutation profile of the
Spike protein typical of the Omicron strain, and have several other mutations in the viral genome. They have been reported since February 2022, in South Africa. Their spread has been very rapid, all over the world, including the United States (Figure 1) and most European Union countries. Compared with the other variants, BA.5 has a growth advantage, leading it to become the dominant variant.
Figure 1.17-day moving average of SARS-CoV-2 cases, COVID-19 hospitalizations and in-hospital
deaths in South Africa, March 5, 2020 to January 22, 2022. From: Jassat et al., 2022.
With the spread of BA.4 and BA.5, cases of COVID-19 have obviously increased, first in South Africa and then in the US and Europe. There is no indication that BA.4 and BA.5 are associated with greater severity of infection than the earlier Omicron variants. Indeed, the upward trend in cases and hospitalizations in the first three South African waves shifted into the Omicron wave, which saw a higher and more rapid peak but fewer hospitalized patients, less clinically severe disease, and a lower case-fatality ratio than the previous three waves (Figure 2). Omicron marked a change in the SARS-CoV-2 epidemic curve, clinical profile, and deaths in South Africa, indicating that the emergence of the new Omicron variants is associated with a gradual decrease in COVID-19 disease severity. The data observed in South Africa are even more significant when taking into account the low percentage of vaccinated populations (about 36%) compared to populations in European states and the US (>75%).
Figure 2. Estimated proportions of circulating variants, showing that cases positive for Omicron BA.4 and BA.5 variants are growing rapidly in the US. From: https://covid.cdc.gov/covid-data-
The BA.4 and BA.5 subvariants substantially escaped neutralizing antibodies induced by both vaccination and infection, indicating that the Omicron variant of SARS-CoV-2 has continued to evolve by acquiring an increasing ability to escape neutralization capacity by prior immunization. These findings immunologically explain the observation of new spikes in COVID-19 cases caused by BA.4 and BA.5 subvariants in populations with high frequencies of vaccination and/or BA.1 or BA.2 infection.
Conclusions and future prospects
New variants of the SARS-CoV-2 coronavirus will continue to emerge, as has always been the case with all other respiratory viruses. As coronavirus infection spreads to ever larger strata of the world's population, widespread herd immunity is likely to set in and protect, through mechanisms of immunologic cross-reactivity, even from newly emerging variants, at least partially. If this is the case, the SARS-CoV-2 pandemic should show an attenuation of lethality in the coming years. Already these months, with the spread of the Omicron variant, we note that while the number of coronavirus-positive cases has increased sharply, the mortality rate has remained low and generally without upward trends.
In any case, scientific research on new vaccines, either based on viral antigenic determinants (epitopes) that show little tendency to mutate, while presenting an adequate immunological reactivity, or based on new vectors and new methods of administration, such as the vaccines based on probiotics that we are developing, could allow to control the emergence of new variants of coronavirus and prevent new planetary emergencies, reducing the impact on national health systems and promoting the health and welfare of the population.
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