From Alpha to Delta, Why Virus Mutations Cause Alarm

(Bloomberg) -- Viruses mutate all the time, including the SARS-CoV-2 coronavirus that’s caused the Covid-19 pandemic. Although most genetic changes are innocuous, some can make the mutant more adept at infecting cells, for example, or evading antibodies. Such “fitter” variants can outcompete other strains, so that they become the predominant source of infections. A succession of more-transmissible variants has emerged over the past year, each harboring a constellation of mutations. The most worrisome so far is the so-called delta variant. It has spread to more than 100 countries since it was first reported in India in October, leading to surges in cases and hospitalizations, especially in places where less than half the adult population has been fully immunized. It’s the dominant strain now in many countries, including in the U.K. and the U.S.

1. What’s a variant?

During replication, a virus often undergoes genetic changes that may create what are called variants. Some mutations weaken the virus; others may yield an advantage that enables it to proliferate. If changes produce a version with distinctly different physical characteristics, the variant may be co-termed a strain. A variant that deviates significantly from its viral ancestors may be identified as a new lineage, or branch on the evolutionary tree. In general discourse, however, the terms are often used interchangeably.

2. What are the most worrisome ones?

The World Health Organization uses “variants of concern” to signify strains that pose additional risks to global public health, “variants of interest” for those that warrant close monitoring because of their emerging risk, and “alerts for further monitoring” for a variant that possesses genetic characteristics that indicate it may pose a future risk. Assessments may change depending on the evolving pandemic. For example, three variants of interest -- epsilon, zeta and theta -- were reclassified in early July as alerts. Variants of concern and variants of interest are assigned letters from the Greek alphabet for identification. As of July 7, the WHO has identified four in each category:

Alpha

This variant emerged in England in September 2020 and drove a winter surge in cases that sent the U.K. back into lockdown in January. Other countries, particularly in Europe, followed the U.K. in reimposing movement restrictions. Alpha was previously the dominant strain in the U.S., and has been reported in at least 173 countries, according to the WHO. The strain may pose a more serious threat to women. Female Covid patients are more likely to require intensive care and have a slightly higher chance of dying from an alpha infection than if they caught another variant, according to an analysis. No such effect was found among males.

Beta

This one, which appeared in South Africa in August 2020, led to a resurgence in Covid cases that overwhelmed southern Africa. It’s been reported in at least 122 countries.

Gamma

This variant, first spotted in the Amazon city of Manaus in December 2020, has contributed to a surge in cases that strained Brazil’s health system and led to oxygen shortages. It’s been reported in at least 74 countries.

Delta

This fast-spreading variant stoked a dramatic wave of Covid cases in India and has since been found in at least 104 countries. It’s estimated to be 55% more transmissible than alpha and almost twice as infectious as the original strain from early 2020. That may be because those infected with the variant can have significantly more infectious viral particles in their airways compared with individuals infected with other strains. Doctors in India have linked delta to a broader array of Covid symptoms, including hearing impairment, and early data from Scotland found Covid patients infected by delta were 1.8 times more likely to hospitalized than those with an alpha infection. Other evidence found delta had some propensity to evade antibody-based treatments and carries an increased risk of reinfection in people who have recovered from Covid caused by another strain.

3. How do variants affect the vaccines?

Scientists pay the most attention to mutations in the gene that encodes the virus’s spike protein, which plays a key role in its entry into cells and is targeted by vaccines. The four variants of concern all carry multiple mutations affecting the spike protein. That raises questions about whether people who have developed antibodies to the “regular” or “wild type” strain -- either from a vaccine or from having recovered from Covid -- will be able to fight off the new variants. In most instances, the variants of concern do lead to a reduction in vaccine effectiveness of varying degrees, though the shots mostly retain their ability to protect against severe disease, according to the WHO. University of Florida researchers found that for the Covid vaccines being rolled out on a global scale, the alpha strain led to “somewhat reduced” efficacy compared with the wild strain, while the beta and gamma variants led to considerably lower efficacy, they said in a paper released in May ahead of peer-review, in which research is scrutinized by experts in the same field before publication. As for delta, data from Public Health England indicate that vaccines are less effective at preventing symptomatic disease compared with alpha, especially after only one dose.

Other research indicates that even if there is a decrease in antibodies, another part of the immune system may counter the coronavirus: T cells from people who have recovered from Covid or received so-called mRNA vaccines from Moderna Inc. or from Pfizer Inc. and its partner BioNTech SE are still able to recognize several variants, negating the virus’s ability to cause severe disease, researchers at the La Jolla Institute for Immunology said.

4. Are some vaccines better?

No randomized clinical trials have directly compared the ability of different vaccines to protect against the original strain, let alone variants. Still, emerging data suggest there will be differences in efficacy. Research by Public Health England released before peer review and based on patient records found two doses of the AstraZeneca Plc vaccine were less effective at preventing Covid from delta compared with a double dose of the Pfizer-BioNtech vaccine.

Public Health England also found that a single dose of the Pfizer-BioNTech shot did a better job at protecting against hospitalization with the delta variant than the AstraZeneca vaccine. Effectiveness was similar after two doses, though.

Elsewhere:

• Research suggests optimal immunity is established when two doses of the AstraZeneca vaccine are given three months apart -- much longer than the recommended three weeks for Pfizer-BioNTech. The finding corresponded with data from the Francis Crick Institute, published in The Lancet, that underscored the importance of a second vaccine dose for increased protection against delta and suggests that more booster immunizations might be needed, especially for vulnerable groups such as organ transplant recipients and those over 80.
• Johnson & Johnson said that its single-shot vaccine neutralizes the delta variant and provides durable protection against infection more broadly.
• In Chile, where Sinovac Biotech Ltd.’s CoronaVac vaccine was administered alongside the Pfizer-BioNTech shot, researchers found a substantial difference in protection against symptomatic Covid at a time when alpha and gamma were the variants most frequently detected. Both inoculations provided a high level of protection against severe disease and death, according to a study published July 7 in the New England Journal of Medicine.

5. Could different vaccines be used in combination?

Yes. That’s already happening to a limited extent, largely because of pauses in the use of AstraZeneca’s vaccine prompted by cases of rare blood clots associated with it. Germany’s vaccine authority has recommended that people who were vaccinated with the AstraZeneca shot get mRNA vaccines as their second. A few small studies, with results not yet peer-reviewed, have suggested that administering a dose of one Covid vaccine followed by a second dose of a different type of Covid shot could be more protective than two doses of the same formulation. Additional studies of vaccine mixing are underway. Such trials could be useful in optimizing the deployment of available inoculations, according to the WHO.

6. Are there other worrisome variants?

New delta variants have been reported in several countries including India, the U.K. and Vietnam. A strain that includes the K417N mutation -- dubbed delta-plus in India -- has stoked some concern, since that genetic change is also harbored by the beta strain that’s associated with an increased risk of reinfection. U.K. researchers said in late June that there’s no evidence yet to suggest the additional mutation is more worrisome. The WHO notes that variants may independently acquire the same or similar mutations that offer a competitive advantage -- a phenomenon known as “convergent evolution” that’s been repeatedly observed over the course of the pandemic. The agency has also highlighted the risk that more variants will emerge given the ongoing high rates of transmission globally.

7. What are drugmakers doing?

Sarah Gilbert, a professor of vaccinology at the University of Oxford who conducted the initial research on the AstraZeneca Plc vaccine, told the BBC that “efforts are underway to develop a new generation of vaccines that will allow protection to be redirected to emerging variants as booster jabs.” Pfizer said it plans to request U.S. emergency authorization in August for a third booster dose of its vaccine, based on initial data from an early study showing an extra dose is safe and can raise neutralizing antibody levels 5 to 10 fold. Several other drug companies have said they’re working on either a booster or combination shot, and the U.K., and some countries in Asia and the Middle East have announced plans to use them. Such alterations aren’t unheard of -- it happens annually with vaccines against flu, which evolves quickly. Unlike flu, coronaviruses have a genetic self-correcting mechanism that minimizes mutations.

8. Are there any other implications?

Yes. There are implications for treatments, diagnostics and the spread of SARS-CoV-2 in animals.

• TREATMENTS: Researchers in South Africa found a theoretical risk that some antibodies being developed to treat Covid could be ineffective against the beta variant. But studies at Columbia University supported tests by Regeneron Pharmaceuticals Inc. showing that its antibody cocktail, which was granted emergency-use authorization in the U.S. and administered to then-President Donald Trump, is effective at neutralizing that variant as well as alpha. Drugmakers are using combinations of antibodies that target separate features of the virus to decrease the potential that so-called virus-escape mutants emerge in response to pressure from a single-antibody treatment.
• DIAGNOSTICS: The U.S. Centers for Disease Control and Prevention has said new strains might undermine the performance of some diagnostic tests that use a process called reverse transcription polymerase chain reaction (RT-PCR) to amplify the virus’s genetic material so that it can be studied in detail. A German study on rapid antigen tests -- which are faster, cheaper and more accessible but less sensitive -- found comparable performance in detecting the alpha, beta and wild-type variants.
• ANIMAL HOSTS: Researchers at France’s Pasteur Institute showed that the beta and gamma variants are capable of infecting common laboratory mice and replicating at high concentrations in the lungs -- a feat that strains circulating earlier weren’t able to do. This raises the possibility of mice or other rodents living close to humans becoming reservoirs for SARS-CoV-2 in regions where the variants circulate, with the strains evolving and potentially spilling back to humans, the researchers said in a March 18 paper released prior to peer review.

The Reference Shelf

• Related QuickTakes on vaccine nationalism, Covid vaccine reactions and mRNA vaccines.
• Summaries of important SARS-CoV-2 lineages by researchers at the University of Edinburgh and their collaborators.
• The WHO answers questions on virus evolution and details knowledge gaps and research in an R&D Blueprint.
• The Lancet and the Journal of the American Medical Association offer perspectives on the variants.
• A location tracker from Scripps Research monitors variants in locations with lineage and mutation reports.
• Bloomberg News talks to the scientists racing to decode the variants.
• The World Health Organization’s weekly updates and the U.S. CDC’s reports.

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