Why the Mutated Coronavirus Variants Are So Worrisome

(Bloomberg) -- Viruses mutate all the time, including the coronavirus that’s caused the global Covid-19 pandemic. Although most of the changes are innocuous, some specific mutations have sparked alarm, and four variants that emerged in the U.K., South Africa, Brazil and India have caused particular concern as they spread worldwide. Studies suggest they are more contagious and some evidence points to one of them being more deadly. At least one other is driving reinfections. Developers are working on second-generation vaccines after early data indicated AstraZeneca Plc’s inoculation may be less effective against some variants. Other data suggest so-called mRNA vaccines -- the novel types made by Pfizer-BioNTech and Moderna -- may offer broader protection.

1. What’s a variant?

During replication, a virus often undergoes genetic changes that may create what are called variants. Some genetic mutations weaken the virus; others may yield an advantage that enables the variant to proliferate. Variants with distinctly different physical characteristics 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 the term “variants of concern” to signify strains that pose additional risks to public health, and “emerging variants of interest” for those that warrant close monitoring because of a potential risk. These have been assigned codes by the various research groups and public health agencies investigating them. As of May 31, the WHO has identified four variants of concern and six variants of interest, and assigned them letters from the Greek alphabet. These are:

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 followed, particularly in Europe. It became the dominant strain in the U.S. in early April, and has been reported in at least 149 countries as of May 25, according to the WHO.

Beta

This one, which appeared in South Africa in August 2020, led to a resurgence in Covid-19 cases that overwhelmed southern Africa. As of May 25, it’s been reported in at least 102 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. As of May 25, it’s been reported in at least 59 countries.

Delta

First identified in India in October 2020, it was found in at least 54 countries as of late May. It’s possibly as much as 50% more transmissible than the alpha variant, the U.K.’s Scientific Advisory Group for Emergencies said on May 13. Public Health England said in its June 3 report that early data from both England and Scotland suggest an increased risk of hospitalization with delta compared to alpha. Other evidence also showed some propensity to evade antibodies, including bamlanivimab, a monoclonal antibody therapy developed by AbCellera Biologics Inc. and Eli Lilly & Co.

3. What effect will those variants have on vaccines?

No clinical studies have directly compared different vaccines and their ability to protect against the original virus strain, let alone variants of concern. Still, data from vaccine trials suggest there will be differences in efficacy across vaccines and variants. For instance, University of Florida researchers found protection against symptomatic infections averaged 86% for alpha, 56% for beta and 61% for gamma. The alpha strain led to “somewhat reduced” efficacy compared with the “wild type” strain, they said in a paper released on May 20 ahead of peer-review and publication. In contrast, the beta and gamma variants led to considerably lower vaccine efficacy, owing to mutations that affect immune function, they said. Other research indicates that two doses of vaccine may still protect against severe Covid-19.

Public Health England on June 3 said evidence indicated a reduced effectiveness of about 15% to 20% after one dose against the delta strain, which is now predominant there, compared to alpha. However, it said there was a “high level of uncertainty around the magnitude of the change in vaccine effectiveness” after two doses of the AstraZeneca vaccine.

4. What are the concerns with these variants?

Broadly, these relate to their:

• Transmissibility, or propensity to spread
• The severity of illness they cause
• Neutralization capacity, or the likelihood they will infect people who have recovered from a previous bout of Covid-19, and
• Potential impact on vaccination through their ability to evade the protection that immunizations are designed to generate

A risk assessment of variants of concern is summarized below:

5. Are there other worrisome variants?

A new delta variant that also has a mutation found in alpha was identified in May in Vietnam, where it’s been blamed for a surge in cases. The WHO said it’s investigating. In France, another variant, B.1.616, was associated with more-severe disease and higher mortality in a small study of hospital patients released ahead of peer review and publication. The authors noted that the strain also may be harder to detect using some testing techniques, which could be due to an altered tropism, or infection pattern, requiring sampling of the lower respiratory tract. B.1.616 was on the WHO’s variant of interest list for awhile, but dropped off in late May, while a strain related to delta -- called kappa -- was added. The WHO has highlighted the risk that more will emerge as the coronavirus continues to spread.

6. How are the variants increasing transmission?

They appear to have advantages that enable them to quickly predominate, although factors such as people congregating indoors more in colder weather may also have contributed to the spread. Infectivity may be increased by mutations that allow the virus to bind better to the receptors on human cells, lowering the concentration of viral particles needed for infection to occur. Writing in the Lancet in mid-May, researchers at Stanford University found that the alpha variant bound to the receptor, known as ACE2, 1.98-times better and beta 4.62-times better than the original virus that emerged in China at the end of 2019.

• A U.K. advisory group said in December that the alpha variant may result in an increase in the basic reproduction number, or R0 (the average number of new infections estimated to stem from a single case) in the range of 0.39 to 0.93 -- a “substantial increase.” That’s been associated with higher concentrations of the virus, or viral load, in the upper airway of acutely infected patients.
• A study released ahead of peer-review and publication of three outbreaks among preschool-age children in Germany indicated that infants ages 1 to 5 who were infected with the alpha variant were as susceptible and infectious as adults infected with that variant in both kindergarten and household settings.
• The gamma variant may be 1.7–to-2.4-fold more transmissible, scientists from Brazil estimated in a study published April 14 in Science.

7. Are some mutations more important?

Yes. Scientists pay most attention to mutations in the gene that encodes the virus’s spike protein, which plays a key role in viral entry into cells. Targeted by vaccines, this protein influences immunity and vaccine efficacy. 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” strain -- either from a vaccine or from having recovered from Covid-19 -- will be able to fight off the new variants.

8. 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, if it turns out that it is necessary to do so.” Pfizer Inc. and its German partner BioNTech SE, as well as Moderna Inc., have said their results indicate their vaccines should still work against the strain detected in South Africa, despite the reduced potency. Moderna later announced that its Covid-19 booster shots gave positive results against that strain as well as the gamma variant, according to early results from a mid-stage trial. Pfizer and Novovax also have said they’re working on either a booster or combination shot. Such alterations aren’t unheard of -- it happens annually with seasonal flu, which evolves quickly. Unlike flu, coronaviruses have a genetic self-correcting mechanism that minimizes mutations.

9. Could different vaccines be used in combination?

Potentially, yes. The Coalition for Epidemic Preparedness Innovations, or CEPI, announced in January as much as $140 million in funding for research to optimize and extend the use of existing vaccines. This could include “mix-and-match” studies of different shots in combinations that may improve the quality and strength of the immune response. Such studies could be useful in optimizing the use of available inoculations, according to the WHO.

10. 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 for therapeutic use could be ineffective against the variant prevalent there. 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 Donald Trump, is effective at neutralizing that variant and the one first identified in the U.K. Drugmakers are using combinations of antibodies that target separate features of the virus to decrease the potential for so-called virus-escape mutants that could emerge in response to selective 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 PCR-based diagnostic tests. France’s health ministry reported in March that several patients developed tell-tale symptoms in Brittany but tested negative for the virus.
• HOST RANGE: Researchers at France’s Pasteur Institute showed that the variants first detected in South Africa and Brazil are capable of infecting common laboratory mice and replicating at high concentrations in the lungs -- a feat earlier circulating strains weren’t able to do. This abrogation of the species barrier raises the possibility of mice or other rodents living close to humans becoming secondary reservoirs for SARS-CoV-2 in regions where the variants circulate, from where the strains could evolve separately and potentially spill back to humans, the researchers said in a March 18 paper released before the process of peer-review, in which research is scrutinized by experts in the same field, and publication.

The Reference Shelf

• Summaries of important SARS-CoV-2 lineages by researchers at the University of Edinburgh and their collaborators.
• WHO answers questions on virus evolution and details knowledge gaps and research in a R&D Blueprint.
• The Lancet and the Journal of the American Medical Association offer perspectives on the variants.
• A location tracker from Scripps Research is monitoring 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 CDC’s reports.
• Researchers recommend public health actions to control new SARS-CoV-2 variants.
• Related QuickTakes on how the coronavirus is transmitted, whether a vaccinated person can still spread the coronavirus, the vaccine rollout, whether you can be forced to get vaccinated, why feeling bad after a Covid vaccine jab could be good, and what experts say about delaying the second vaccine shot.

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