Viruses mutate all the time, including the coronavirus that’s caused the global Covid-19 pandemic. Although most of the changes are innocuous, several mutants have sparked alarm, and three variants that emerged in the U.K., South Africa and Brazil 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 and two others driving reinfections. Developers are working on second-generation vaccines after early data from South Africa indicated AstraZeneca Plc’s inoculation was less effective against the variant circulating there.

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 variants?

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 their potential risk. These have been assigned names or codes by the various research groups and public health agencies investigating them. As of May 11, the WHO had identified four variants of concern and six variants of interest. These are:

B.1.17/VOC 202012/01

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 149 countries as of May 11, according to the WHO.

501Y.V2/B.1.351

This variant, which appeared in South Africa in August 2020, led to a resurgence in Covid-19 cases that overwhelmed in southern Africa. As of May 11, it’s been reported in 102 countries.

P.1

This variant, first spotted in the Amazon city of Manaus in December, has contributed to a surge in cases that’s strained Brazil’s health system and led to oxygen shortages. As of May 11, it’s been reported in 60 countries.

B.1.617

The B.1.617 lineage identified in India in October is the latest to be designated a variant of concern by the WHO, based on early evidence suggesting it has higher rates of transmission, and some propensity to evade antibodies, including bamlanivimab, a monoclonal antibody therapy developed by AbCellera Biologics Inc. and Eli Lilly & Co. It was detected in 44 countries as of mid-May, and spawned three versions -- B.1.617.1, B.1.617.2 and B.1.617.3 -- amid a dramatic spike in cases. Of these, the B.1.617.2 strain has been identified as particularly worrisome. It’s “highly likely that this variant is more transmissible than B.1.1.7” and possibly as much as 50% more transmissible, the U.K.’s Scientific Advisory Group for Emergencies said on May 13. Modeling indicates such a transmission advantage nationally would lead to a resurgence of hospitalizations, potentially exceeding previous peaks, if plans to end a lockdown progress at the fastest proposed pace, the scientific panel said. It also flagged a potential reduction in protection given by vaccines or by naturally acquired immunity from past infection. Data are still emerging, and any impact on effectiveness of vaccines or therapeutics, or reinfection risks remain uncertain, the WHO said on May 11.

3. Are there other worrisome variants?

In France, the B.1.616 variant 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. The WHO said on April 20 that 19 other variants are under investigation, and highlighted the risk that more variants of global importance will emerge in the coming months.

4. How quickly have the strains spread?

Rapidly, aided initially by year-end holidays traditionally associated with family and social gatherings. Insufficient surveillance in most countries, including the U.S., has obscured recognition of variants circulating in many places.

5. What are the concerns with these variants?

Broadly, they pose concerns of varying degrees. 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

The WHO’s assessment summarized:

Several studies assessing the B.1.1.7 variant’s propensity to cause more severe illness and an increased fatality rate have reported contradictory findings, with some finding no difference in severity compared with the original strain from Wuhan, China, and one estimating a 55% higher mortality risk.

6. How are the variants increasing transmission?

They appear to have some advantage over other versions that has enabled them to quickly predominate, although factors such as people congregating indoors more in colder weather may also contribute to spread. The U.K. strain has acquired 17 mutations compared with its most recent ancestor -- a faster rate of change than scientists typically observe. A U.K. advisory group said in December that the B.1.1.7 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. The P.1 variant may be 1.7–to-2.4-fold more transmissible, scientists from Brazil estimated in a study published April 14 in Science. The international spread of all three variants of concern has helped drive a rebound in Covid-19, with the number of new cases reported worldwide increasing each week since mid-February.

7. How many mutations are there?

Many thousands of mutations and distinct lineages have arisen in the SARS-CoV-2 genome since the virus emerged in late 2019. A variant with a so-called D614G mutation emerged in early 2020. By June, it had replaced the initial strain identified in China to become the dominant form of the virus circulating globally. Months later, a novel variant linked to farmed mink was identified in a dozen patients in North Jutland, Denmark, but doesn’t appear to have spread widely. As SARS-CoV-2 continues to circulate, more mutations will arise, potentially leading to more variants.

8. Are some mutations more important?

Yes. Scientists pay most attention to mutations in the gene that encodes the SARS-CoV-2 spike protein, which plays a key role in viral entry into cells. Targeted by vaccines, this protein influences immunity and vaccine efficacy. The B.1.1.7, 501Y.V2, P.1 and B.1.617 variants 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.

9. What do we know so far?

In January Public Health England found those previously infected with the “regular” coronavirus are likely to mount an effective antibody response against the B.1.1.7 variant. But the same month the first known instance of a recovered Covid-19 patient being reinfected with the P.1 variant was reported in Brazil. That strain has several key mutations in common with the 501Y.V2 strain from South Africa, that was associated with some 4,000 reinfections in people who had already experienced Covid-19 in an earlier epidemic. In a Jan. 28 editorial in the Journal of the American Medical Association, virologist John P. Moore and vaccinologist Paul Offit described the 501Y.V2 variant as “more troubling” because of its potential for reducing vaccine efficacy, due to its particular spike-protein mutations.

10. How effective will vaccines be?

Data are emerging, and no clinical studies have directly compared different vaccine types and their ability to protect against the new strains. Overall, a dozen vaccines have proved effective in clinical trials at preventing severe disease and death from Covid-19. The studies suggest, however, that some may not be as good at stopping less severe illness in countries where particular variants predominate. Notably:

• Two studies from Israel and another from Qatar offer further evidence that the Pfizer-BioNTech vaccine provides similar protection against Covid-19 caused by B.1.1.7 disease, as reported in clinical trials.

• A published study from Israel estimated effectiveness for the Pfizer-BioNTech vaccine 14 days or more after a second dose of

• death: 98.1%

• hospitalization: 98.0%

• symptomatic disease: 97.7%

• infections: 96.5%

• asymptomatic infection: 93.8%

• A study from Qatar reported effectiveness of the Pfizer-BioNTech vaccine to be 89.5% against documented B.1.1.7 infection and 100% against documented B.1.1.7 severe disease 14 days or more after the second dose. The study also evaluated effectiveness of the Pfizer BioNTech-vaccine against B.1351-specific disease, finding a reduced effectiveness of 75.0% against infection 14 days or more after the second dose. However, effectiveness against severe disease was 100%.

• A study from the U.S. conducted when B.1.1.7 was circulating found the Johnson & Johnson vaccine was 76.7% effective against infection, similar to clinical trial efficacy findings conducted in a non-B.1.1.7 setting.

• Shots from both Novavax Inc. and Johnson & Johnson showed lower efficacy in South Africa compared with other countries.

• South Africa announced plans in early February to halt its rollout of the AstraZeneca vaccine. An interim analysis of clinical trial results there found two doses of the vaccine didn’t protect recipients against mild-to-moderate Covid-19 from the 501Y.V2 variant, though researchers speculated that the regimen might still protect against severe illness. A WHO advisory panel cautioned that the 21-to-35-day interval between the first and second doses isn’t optimal for inducing immunity and larger studies are needed.

11. What are drugmakers doing?

Sarah Gilbert, a professor of vaccinology at the University of Oxford who conducted the initial research on the AstraZeneca vaccine, said 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.” The new shot could be ready for the fall, she told the BBC. Pfizer and its German partner BioNTech, as well as Moderna, have said their own results indicate their vaccines should still work against the strain detected in South Africa, despite the reduced potency. Moderna announced in early May that its Covid-19 booster shots gave positive results against the 501Y.V2 and P.1 variants, 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.

12. 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 additional clinical 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, including the AstraZeneca shot, according to the WHO.

13. 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 501Y.V2 variant prevalent there. But studies at Columbia University support 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 501Y.V2 and the variant first identified in the U.K. Drugmakers are using combinations of antibodies that target separate features of SARS-CoV-2 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 mid-March a variant spreading in Brittany, where several patients developed tell-tale symptoms 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.

(Updates to add detail on B.1.617 lineage in section 2.)

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