COVID-19 Emerging Variants

Containing the COVID-19 pandemic requires monitoring the rapidly emerging variants of the virus. As of spring 2021, there were more than a dozen variants being evaluated by the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC). Fortunately, none of these is a variant of high consequence, a classification that would indicate that prevention measures or medical countermeasures have significantly reduced effectiveness. Although current vaccines are very effective, manufacturers are focused on developing strategies to ensure that new and booster vaccines can keep pace with the rapid rate of mutation and maintain the highest level of protection.


Coronaviruses are a diverse family of positive-sense single-stranded RNA-enveloped viruses. The virus infects mammals, including humans, avian, and other animal species. The Coronaviridae consist of four genera: alphacoronavirus, betacoronavirus, gammacoronavirus, and deltacoronavirus. Infection in mammalian species is exclusively by alphacoronaviruses and betacoronaviruses.1 Sequencing of the full-genome and phylogenetic analysis reveal that COVID-19 is caused by a betacoronavirus within the same subgenus as the severe acute respiratory syndrome virus (SARS). Early on, the Coronaviridae Study Group designated the novel virus that emerged from Wuhan, China, late in 2019 as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).2


Like other infectious coronaviruses, the initial sequence of infection from SARS-CoV-2 involves binding of the spike (S) protein to the cellular entry receptors of the host. The expression and distribution of these entry receptors influence viral pathogenicity. Three receptors are commonly associated with coronavirus to human infectivity and pathogenesis: human aminopeptidase N (APN; HCoV-229E), angiotensin-converting enzyme 2 (ACE2; HCoV-NL63, SARS-CoV and SARS-CoV-2), and dipeptidyl peptidase-4 (DPP4; MERS-CoV).3

The receptor of interest associated with SARS-CoV-2 is the ACE2 receptor, which is ubiquitous and found virtually in all organs; there is abundant surface expression of ACE2 receptors on lung alveolar epithelial cells and enterocytes of the small intestine.4 Once the SARS-CoV-2 virus binds to the host ACE2 receptor, intracellular fusion is assisted by the TMPRSS2, a surface serine-protease. The intracellular viral replication cycle begins by uncoating and releasing the >30 kb mRNA strand, where the genetic sequence containing 10 genes is immediately translated to the viral replication and transcription complex and further produces a total of 26 proteins. The result is virions secreted from the infected cells by exocytosis (Figure 1).5

FIGURE 1  |  SARS-CoV-2 Replication Cycle

(A) SARS-CoV-2 viral particle (B) SARS-CoV-2 spike protein bind to ACE2 surface receptor and TMPRSS2 prime viral spike protein for cellular entry (C) Uncoating of viral particle in the cytosol and translation of proteins required for viral replication and transcription complex (D) Biogenesis of viral organelles replication complex that translate viral mRNA to structural protein that translocate into the Endoplasmic Reticulum (E) From the ER, the protein translocate to Golgi for post-processing to a mature viral particle before exocytosis

Source: V’kovski P, et al. Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol 2021 Mar;19(3):155-70.


Mutations are defined as changing a gene, resulting in a variant form transmitted to subsequent generations. Mutations are common in viruses. The capacity of viruses to adapt to the host and environment is dependent on the ability of the virus to generate diversity in a short period of time. In terms of viral mutation rates among the different types of viruses, RNA viruses can mutate faster than DNA viruses, and there is a negative correlation in mutation rate versus the size of the genome. These viral mutation rates are normally represented as the rate of substitution per nucleotide per cell infection cycle (s/n/c).6 Coronaviruses are the exception to the rapid viral mutation rate seen in other smaller RNA viruses such as influenza.

Coronaviruses such as SARS-CoV-2 contain within their large(>30 kb) genome a region to encode for an RNA-dependent RNA-polymerase, a proofreading mechanism to reduce the mutation rate and stabilize the genome. Betacoronaviruses accumulate around 10-6 (s/n/c) mutations in each round of replication compared to the 14 kb influenza virus, which has a mutation rate of approximately 10-5 (s/n/c) or 10 times the mutation rate for coronavirus.7

Although most of the mutations found on the SARS-CoV-2virus are benign, specific mutations on the spike protein can enhance the adaptability and transmissibility of the virus. More importantly, mutations on the spike protein can be concerning considering that this region houses the receptor-binding domain (RBD) — the contact region to the host cellular entry receptor. Mutations are represented by an amino acid residue number indicating the location of the amino acid sequence. The location for the RBD for SARS-CoV-2 is between amino acid residues 319 and 541, with the receptor-binding motif located between amino acid residues 437 and 508.8

The first recognized mutation that altered the fitness of the SARS-CoV-2 virus was the D614G mutation found on the spike protein, which enhanced the infectivity and stability of the virions. Before May 2020, the D614G mutation was rare but quickly became the dominant circulating strain of SARS-CoV-2, occurring in more than 74 percent of all published sequences by June 2020. Nearly all specimens sequenced today contain the D614G mutation.9


Monitoring variants is essential to containing the COVID-19 pandemic. As an example, the genomic database GISAID is an international collaboration of genetic data aggregation and identification. The most significant value is the ability of these databases to identify and monitor emerging variants with criteria from organizations such as the WHO and CDC. Unfortunately, the sharing of SARS-CoV-2 genome data continues to lag. As an example, the United States only uploaded 1.6% of COVID-19 cases to GISAID in March 2021.10

As of spring 2021, there were more than a dozen circulating variants of SARS-CoV-2. Three classifications of these variants are closely monitored by the CDC and WHO. Variants of interest are variants with genetic markers associated with changes in the RBD, reduced neutralization by antibodies, reduced efficacy of treatments, predicted increase in transmissibility or disease severity, or potential diagnostic impact. Variants of concern demonstrate significant increase in transmissibility, more severe disease, reduction in neutralization by antibodies, reduced effectiveness of vaccines, or diagnostic failure. Fortunately, none of the current variants meet criteria for the third classification, variant of high consequence. The variant of high consequence classification is reserved for viral variants with clear evidence that prevention measures or medical countermeasures have significantly reduced effectiveness.

Globally, per the WHO, in May 2021, there were four primary variants of concern: B.1.1.7, B.1.351, P.1, and B.1.617.2 (Figure 2). The variant B.1.1.7 was initially detected in the United Kingdom in September 2020. The B.1.351 and P.1 variants are similar but have different origins. B.1.351 emerged from South Africa around September 2020, and P.1 was detected in early December 2020 in travelers from Brazil to Japan. The B.1.351 and P.1 have three mutations on the RBD (N501Y, E484K, and K417N/T). Of note, the mutation at the E484K position appears in three of the SARS-CoV-2 variants of concern — a pattern of convergent evolution where the trait emerges in different independent lineages over time as the virus adapts to similar environments. There is evidence that the mutation improves the virus fitness in some way by either evading neutralizing antibodies or reducing the efficacy of vaccines.

FIGURE 2  |  WHO variants of concern as of May 2021

The other emerging variant of concern, B.1.617.2, was first discovered in India in December 2020 and quickly spread throughout the country. It contains two key mutations, L452R and T478K. These two mutations were not discovered together before being identified in the B.1.617.2 variant. The L452R mutation is the same mutation found in the B.1.427 and B.1.429 strains, which demonstrate an approximately 20 percent increase in transmissibility compared to the original Wuhan strain, along with a twofold increase in viral shedding.11 The B.1.617.2 variant has mutations associated with an increase in transmissibility and ability to evade the immune responses. Early studies suggest that convalescent sera from patients infected with SARS-CoV-2 was 50 percent less effective against B.1.617.2. Antibodies from participants vaccinated with the Pfizer vaccine were 67 percent less potent against the B.1.617.2.12 Figure 2 summarizes the WHO variants of concern and important mutation characteristics.


The adenovirus-vector vaccine ChAdOx1 from AstraZeneca only found 10% protection against mild-to-moderate disease from the B.1.351 variant, but demonstrated 75 percent protection against the B.1.1.7variant, demonstrating the importance of understanding vaccine efficacy with respect to circulating variants.13 Another adenovirus-vector vaccine from Janssen also showed differing efficacy based on the region and associated circulating variants.14

Moderna and Pfizer vaccines are both authorized mRNA vaccines with greater than 90 percent efficacy against SARS-CoV-2 observed in the clinical trials.15,16 However, SARS-CoV-2 variants have changed over time, and the currently circulating predominant variant differs compared to the time period of the phase 3 clinical trials; in vitro studies suggested a four- to sixfold reduction in neutralizing antibody response against variants with the E484K mutation.17,18,19


Public health and nonpharmaceutical interventions remain two of the most effective ways to control the spread of the SARS-CoV-2 virus and its variants. Vaccines remain the greatest hope at stopping the pandemic, and booster vaccination will likely be required to help protect against emerging variants.

Vaccine manufacturers are employing different strategies to evaluate booster doses of COVID-19 vaccines. Pfizer-BioNTech is evaluating a booster dose of the same vaccine against the variants, hoping that the increase in antibody production and associated immune system priming will be effective at preventing infection from the variants, while Moderna is exploring booster vaccine candidates based on the B.1.351 genetic sequence.

Unlike the traditional vaccine platforms, the mRNA vaccines are agile in terms of adaptability and speed of development. Additionally, mRNA vaccines have inherent adjuvant properties that enhance the response of the antigen-presenting cell. Once the target vaccine antigen is identified, the genetic information is sequenced and converted to an mRNA sequence that encodes the target antigen. The process from antigen identification to mRNA vaccine candidate can occur in just eight days.20

Indeed, several questions remain on the first-generation COVID-19 vaccines and their efficacy against the variants. The immune response, along with which elements are associated with protection against infection, remains incompletely understood. The correlates of protection from the different vaccines still need to be determined.

The WHO recently proposed a framework for expediting new vaccine development. One intriguing proposal is using pooled safety data on products sharing the same platform, to avoid the need for lengthy, costly, and challenging clinical studies. The proposal is in line with European Medical Association guidance on adapting the second generation of vaccines to the variants.

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