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To a world that has become weary, yet accustomed to playing defense against SARS-CoV-2, evolution of the Delta variant is both unwelcome and unsurprising. , was first identified in India in Dec. 2020. Within a matter of months, this particular variant spread to over 98 countries around the world, becoming the dominant variant in more than a dozen of those countries, including India, the U.K., Israel and the °®¶¹´«Ã½ States. Delta is now responsible for more than being reported in the U.S. and, with only 48% of the total U.S. population fully vaccinated, conditions are ripe for continued evolution and spread of SARS-CoV-2. Three foundational questions continue to drive research with each new variant that’s identified.

1. How Contagious Is the Delta Variant?

Data indicate that Delta is and almost twice as transmissible as the original Wuhan strain of SARS-CoV-2. Furthermore, significantly more viral particles have been found in the airways of patients infected with the Delta variant. A Chinese study reported that than those in infections caused by other variants. In response to this information, the World Health Organization (WHO) regards Delta as “” variant so far.

2. Is the Delta Variant More Dangerous than Other Variants of Concern?

According to surveys conducted in the U.K., where Delta accounts for ~90% of current COVID-19 cases, symptoms of Delta tend to be a little different than other strains, but that does not necessarily mean the associated symptoms are more severe. Fever, headache, sore throat and runny nose are common, while cough and loss of smell are not. Other reports , including hearing impairment, severe gastrointestinal issues and blood clots leading to tissue death and gangrene. Research is ongoing to determine if Delta infection is associated with increased hospitalization and death. One early study assessing the risk of hospital admission in Scotland reported that than in unvaccinated individuals with Alpha.

are once again on the rise in the U.S., especially in and the Delta variant is surging. On July 16, 2021, the Centers for Disease Control and Prevention (CDC) reported a 7-day average increase in new COVID-19 cases of 69.3% and a 35% increase in hospitalizations. Still, it is difficult to determine whether Delta is actually making people sicker than previous forms of the virus or if it is simply circulating amongst more vulnerable populations where case numbers are high, vaccination rates are low and increased stress on hospital systems is impacting patient care and disease outcomes.

What is clear is that the majority of hospitalizations and COVID-19-associated deaths in the U.S. , leading to a chilling warning from CDC director Dr. Rochelle Walensky that “this is becoming a pandemic of the unvaccinated.”

3. Will Vaccines Remain Protective against the Delta Variant?

Studies show that 2 doses of and death, but neutralization levels of vaccinated sera are lower against the Delta variant compared to the original strain. A study published in the New England Journal of Medicine from individuals who had recovered from natural SARS-CoV-2 infection and sera from individuals who had been fully vaccinated with Moderna or Pfizer vaccines against infectious B.1.617.2 virus. Data from the study indicated that, on average, the Delta variant was 2.9 times less susceptible to neutralization than the Wuhan strain, but most convalescent serum samples and all vaccination serum samples showed detectable neutralization activity. As a result, researchers concluded that immunity conferred by mRNA vaccines is likely to be retained against the Delta variant.

These results were supported by research, published in Nature, that against monoclonal antibodies, convalescent sera and sera developed after vaccination. The study found that some antibodies targeting the N-terminal domain and receptor binding domain of the spike protein (S protein) showed impaired binding and neutralization of the Delta variant. Additionally, convalescent sera, collected up to 12 months post-symptoms from individuals who had recovered from natural SAR-CoV-2 infection, were 4-fold less effective at neutralizing Delta than Alpha. Sera from individuals who were partially vaccinated (had received 1 dose of Pfizer or AstraZeneca vaccine) showed little to no neutralizing activity against Delta. Sera from 95% of those who received 2 doses of either vaccine generated a neutralizing response that was 3-5-fold less potent against Delta than Alpha.

Another study published in the New England Journal of Medicine used a test-negative, case-control design to estimate vaccine effectiveness against symptomatic disease caused by the Delta variant, compared to Alpha. The study, which was conducted in the U.K., reported an after 2 doses of mRNA vaccine, but only 30.7% efficacy after 1 dose, which is below the U.S. Food and Drug Administration (FDA)’s 50% efficacy threshold for COVID-19 vaccines.

Initial reports indicated that the , however a new study, not yet peer-reviewed, indicated that sera from a significant fraction of J&J vaccinated individuals showed a , which, according to the study’s mathematical modeling, could result in decreased protection from infection.

Taken together, these data support the importance of full dose vaccination against SARS-CoV-2, but reports of reduced vaccine efficacy against Delta warrant further investigation into breakthrough infections and the possibility of vaccine booster shots. Genomic analysis of isolates from 63 vaccine breakthrough infections in India (not yet peer-reviewed) revealed that B.1.617.2 was the predominant lineage in groups who were partially and fully vaccinated with either AstraZeneca or (an inactivated virus-based vaccine developed by Bharat Biotech in collaboration with the Indian Council of Medical Research).

In late July, 2021, the that were associated with large public gatherings in Barnstable County, Massachusetts. Out of the 469 identified cases of COVID-19, 346 or 74% of them were breakthrough infections that occurred in people who were fully vaccinated with 2 doses of Pfizer or Moderna, or 1 dose of the J&J vaccine. Genomic analysis revealed that Delta was responsible for 90% of the 133 sequenced breakthrough infections. This information prompted the CDC to recommend the use of masks in indoor public spaces, regardless of vaccination status, in areas where COVID-19 transmission is high. Further research into breakthrough infections that occur after COVID-19 vaccination is needed.

Meanwhile, companies are already developing booster doses to improve efficacy against circulating variants. Pfizer plans to seek , which is expected to elicit . However, antibodies alone do not give the whole picture of immune protection. How other vaccine-elicited immune components, such as T cells and B cells, respond when challenged by the Delta variant is still relatively unclear, and conversation about whether booster doses are needed yet are ongoing.

To learn more about the effectiveness of vaccines against Delta and dive deeper into data from the studies mentioned here, tune in to Microbial Minutes, ASM's monthly video series of trending topics in the microbial sciences.

Culpable Mutations of the Delta Variant

Without a doubt, increased transmissibility, coupled with potential increases in disease severity and immune escape, makes Delta especially dangerous. The SARS-CoV-2 spike protein is the main target of COVID-19 vaccines, and most serum neutralizing antibody responses elicited during natural SARS-CoV-2 infection are of S protein. Therefore, if a mutation (or combination of mutations) causes changes to the S protein that are not recognized by first wave antibodies, immunity developed against the reference strain may be ineffective against the new variant. The SARS-CoV-2 Delta variant possesses a combination of S gene mutations that make it particularly worrisome to scientists, including multiple mutations in the receptor binding domain (RBD), a mutation located near the furin cleavage site and a number of mutations in a vulnerable region of the N-terminal domain known as an “.”

Receptor Binding Domain

The receptor binding domain is the portion of the spike protein that binds directly to human ACE2 receptors. Delta has 3 RBD mutations. The first, a lysine to asparagine substitution at position 417, is present in some, but not all sequences of B.1.617.2. It is also common to the Beta variant and has been associated with conformational changes to S protein, which may aid in immune escape. The second mutation, a leucine to arginine substitution at position 452, is common to the , and is known to increase affinity for ACE2 receptors found on the surface of a variety of human cells, including the lungs. And the third, a threonine to lysine substitution at position 478, is common to the B.1.1.519 lineage, and has been predicted to , which may further increase RBD/ACE2 binding affinity and enable immune escape.

Furin Cleavage Site

The spike protein consists of a receptor-binding subunit (S1) and a fusion subunit (S2), which must be cleaved from each other to mediate membrane fusion and cause infection. The is the junction where that cleavage takes place, and Delta contains a proline to arginine substitution (also common to Alpha) near this cleavage site at position 681 that makes the sequence less acidic and causes furin to recognize and cut more effectively. As a result, more spike proteins are primed to enter human cells. Research indicates that less than 10% of spike proteins are primed in the original strain, 50% are primed in Alpha and . The mutation likely increases viral infectivity and transmissibility; however, in order to be consequential.

NTD-Antigenic Supersite

Scientists have of S protein that are especially vulnerable to antibody recognition and attack, called NTD-antigenic supersites. Delta contains a number of mutations that fall within an antigenic supersite, including a threonine to arginine substitution at position 19, a glycine to aspartate substitution at position 142, deletions at positions 156 and 157 and . Accumulated mutations in antigenic supersites are thought to enhance the virus’s ability to avoid immune detection.

Stopping Transmission Is Key to Controlling Variants

Humanity has its hands full as the virus continues to mutate and evolve potential mechanisms to escape the immune defenses its hosts have worked so hard and sacrificed so much to develop. In addition to the variants of concern currently being monitored, researchers are keeping an eye on a number of variants of interest, including . When specific mutations (like K417N/T) become fixed in different virus lineages, it is evidence that natural selection may be occurring. According to Dr. Vaughn Cooper, ASM’s Council on Microbial Sciences-elected Board Director and evolutionary biologist, stopping the virus is key. “The more infections, the more chance that mutations will occur and thus the more likely selection will enrich the best mutations to improve the virus,” he explained. Vaccination is the best weapon in the fight to curb transmission.