Omicron's edge: boosters pressure SARS-CoV-2 to adapt and evolve

Viruses naturally adapt to positive and negative environmental pressures, such as natural or vaccine-induced active immunity or passive immunity mediated by the transfer of antibodies from another individual.

During the coronavirus disease 2019 (COVID-19) pandemic, both active and passive immunizing agents were rolled out. A new study in The Lancet eBioMedicine explores the effects of vaccine booster doses on the adaptive evolution of the virus.  

Study: Selective adaptation of SARS-CoV-2 Omicron under booster vaccine pressure: a multicentre observational study. Image Credit: Naeblys/Shutterstock.com

Background

In 2022, the Omicron variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rose to dominate the global scene. This variant of concern (VOC) has over 60 mutations compared to the ancestral virus.

This phenomenon has been held responsible for the rapid spread and high rate of breakthrough infections with Omicron.

Multiple Omicron subvariants and their sublineages have emerged. Notably, the Omicron spike protein is less efficiently cleaved than other spike variants. As a result, its entry into host cells depends more on the presence of cathepsins and less on TMPRSS2, unlike previous variants. This enables its faster replication in the upper airway rather than the lungs.

As a result, critical illnesses make up a much smaller proportion of the enormous number of Omicron infections globally.

Omicron subvariants are remarkable for their immune evasion, escaping both vaccine-induced and therapeutic antibodies. Many of these subvariants carry recurrent mutations affecting important functional sites, particularly the spike protein.

Such convergent mutations occur against an increasing but incomplete antibody response that cannot neutralize a rapidly evolving virus. This drives the appearance of common or recurrent mutations in different strains. 

Immunologists apply the doctrine of original antigenic sin to explain this, whereby the first spike protein to imprint the immune system leaves its mark on the antibody production process.

As a result, even when other quite different variants are encountered, the antibodies continue to be more strongly directed to the originally targeted antigen, making them less capable of neutralizing the current ones.

With high booster dose coverage, the variants with the most elevated immune escape spread most readily. While breakthrough infections did occur with Delta, this was mostly due to the weakening of antibody levels and minor mutations causing the virus to escape neutralization.

In this case, Omicron rapidly became dominant and has continued to spread and change until the present day.

However, while boosted vaccinated individuals show a doubling of the neutralizing titer with Omicron infection, compared to Delta, the titer is 12-fold higher without booster doses.

The paper seeks to examine the selective adaptation occurring as booster vaccines are being administered on an increasing scale worldwide, coupled with Omicron’s mutational tendencies.

What did the study show?

The study was cross-sectional in which the changes in SARS-CoV-2 due to genetic drift and mutation were identified and examined.

This was conducted for each variant of the virus, categorizing each shift by the vaccine status of the individual, the ancestral descent of the viral strain, and the demographic and clinical characteristics of the participants.

The study included over 5,400 SARS-CoV-2 sequences from documented infections in metropolitan New York from July 2021 to August 2022. The researchers found a shift from predominantly Delta variant infections to mostly Omicron variants (BA.1-BA.5).

The proportion of people who had undergone the primary series of COVID-19 vaccinations went up from 55% to 80%, while those who took the booster dose went up from 0 to 40%.

Of the 5,400 sequences, 35% were from unvaccinated or vaccinated-and-boosted people, with ~30% being from vaccinated non-boosted individuals. Thus, The researchers could compare the effects of high binding antibody levels on the direction and rate of mutations in Delta vs Omicron.

Interestingly, the first booster doses were rolled out on a large scale during the Delta wave, but almost all subsequent breakthrough infections and reinfections were caused by the Omicron variant.

“These data revealed that boosters but not primary vaccination were the main source of vaccine pressure leading to mutational imprints, adaptive evolution, and variant selection during the transition from Delta to Omicron and evolution into Omicron subvariants.”

Further analysis showed that Omicron subvariants BA.2-BA.5 spread faster than other lineages of the same period among booster recipients. This was not the case with BA.2.12.1 or BA.4.

The booster shots produced antibodies selected for Delta spike protein mutations at multiple sites, with 3,000 times as many mutation sites in boosted individuals as vaccinated individuals.

These, however, poorly adapted the virus to spread or survive neutralizing antibodies – diffuse adaptive evolution.

In contrast, the boosters forced Omicron BA.1, at first, and then BA.2, to diversify into BA.2-BA.5 spikes, undergoing large-scale positive selection. These mutations focused almost exclusively on stronger binding at the receptor-binding motif–focused adaptive evolution.

Convergent mutations were especially prominent at the spike site R346X, which allows for immune escape and has been observed in over a hundred lineages.

While mutations were far more common in boosted individuals with Delta infection vs unvaccinated individuals, this slowly shifted to higher mutation scores in unvaccinated vs boosted individuals with Omicron infection.

High negative selection scores were observed with Omicron BA.2-BA.5, but not Delta or BA.1, indicating the rejection of multiple mutations so that the wildtype sequence was restored at those sites.

Both purifying mutations (negative selection) and diversifying mutations (positive selection) are required in balance to arrive at the highest immune escape and viral fitness profile.

Such mutations enabled Omicron spikes to escape immune neutralization, bind the receptors more strongly, or promote spike cleavage. These crucial mutations give them an advantage compared to other variants, explaining why further significant mutations failed to occur.

The fact that such mutations were selected simultaneously “demonstrates that immune escape is not a uni-directional process but intertwined with adaptations to maintain/improve viral transmission, cellular entry, and replication.”

What are the implications?

Antibodies are extremely specific in their recognition and binding of antigens, in this case, the Delta vs Omicron spike antigens. This makes them effective at neutralizing particular variants. It also leaves them open to selection pressures, allowing some subvariants to flourish and spread and new ones to emerge.

Boosters are meant to increase the level of immunity high enough to overcome viral immune escape because of adaptation to vaccine-induced or natural immunity. The current COVID-19 Omicron booster vaccination programs are still underway.

These have promoted the development of BA.2 and BA.5 sublineages and their recombinants, which have dominated COVID-19 cases this year.

The authors conclude:

“Booster shots are a pivotal tool to lift SARS-CoV-2 immunity and are particularly recommended in vulnerable populations and healthcare workers.”

They exert immunological damping of the spread and clinical severity of infections. Still, there is a need to monitor genomes to detect selective adaptation.  

Written by

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.