Why the mutated coronavirus variants are so worrisome

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 UK, 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 another driving reinfections. Vaccine developers are working on new versions 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 mutations that may create what are called variants. Some mutations weaken the virus; others may yield some 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. So far, the WHO has identified three variants of concern and three variants of interest. These are:

• The variant that emerged in England in September 2020, B.1.1.7, contributed to a surge in cases that sent the UK back into lockdown in January. Other countries followed, particularly in Europe. It became the dominant strain in the US in early April.
• In southern Africa, hospitals faced pressure from a resurgence driven by another variant, 501Y.V2.
• Brazilian researchers, meanwhile, have warned that a so-called P.1 variant spotted in Manaus, Amazonas state, in December 2020 may have driven a surge in cases that's strained the health system and led to oxygen shortages.

The WHO said in mid-April it is reviewing whether to add a strain designated B.1.617, first recorded in India in October, to its variant of interest list, as India has done. This one is reported to harbor two key mutations known to reduce -- but not eliminate -- the ability of antibodies generated by either a previous infection or vaccination to fight it.

3. Are there others?

Researchers in Los Angeles reported a novel strain, denoted as CAL.20C in June 2020, that was linked to a late-year surge of coronavirus cases in Southern California. Preliminary research indicates it's slightly more transmissible and may moderately resist antibodies generated from a previous infection, the WHO said on March 16. By then, the strain had been detected in all US states and at least 26 other countries. It's deemed a variant of concern by the CDC. The CDC also has B.1.525, which it identified in New York around the same time as the WHO, as a variant of interest, along with another New York strain (B.1.526) and the P.2 strain, though less is known about them.

4. How quickly have the strains spread?

Rapidly, aided initially by year-end holidays traditionally associated with family and social gatherings. As of April 13, imported cases or community transmission of the B.1.1.7 variant from the UK had been reported in 132 countries, according to the World Health Organization. It also had become the most common strain in the US As of April 13, scientists have found the 501Y.V2 variant that first appeared in South Africa in August 2020 in 82 countries, while 52 countries are reported to have detected the P.1 variant first seen in Brazil. Insufficient surveillance in most countries, including the US, 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

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 UK strain has acquired 17 mutations compared with its most recent ancestor -- a faster rate of change than scientists typically observe. A UK 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. US health officials said in late March that a variant-induced resurgence of cases in some regions could augur a long-feared possibility: That another surge could occur even as states are flinging open vaccine eligibility criteria, trying to get shots in arms as quickly as possible.

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, and P.1 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, which was associated with some 4,000 reinfections in people who had already experienced Covid-19 in an earlier epidemic. In a January 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, 10 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:

• 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.
• A study published February 24 of almost 1.2 million people in Israel, which has inoculated a higher percentage of its population than any other country, estimated that the Pfizer Inc.-BioNTech SE vaccine was 92% effective in preventing all infections. By the end of the surveyed time period, as many as four-fifths of the infections in Israel were caused by the B.1.1.7 variant first identified in the UK
• Scientists at the Fred Hutchinson Cancer Research Center in Seattle found a single jab of either the Moderna or Pfizer-BioNTech shot bolstered the immune response in 10 patients who had recovered from a SARS-CoV-2 infection early in the pandemic. The concentration of neutralizing antibodies in the recipients' blood increased about a thousand-fold, and they appeared potent against the 501Y.V2 variant first identified in South Africa.

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. Nevertheless, Moderna said March 10 that it began testing modified Covid-19 vaccines, designed to address the potential need for booster vaccine candidates, in clinical trial participants. 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 US and administered to Donald Trump, is effective at neutralizing 501Y.V2 and the variant first identified in the UK 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 US 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.

Disclaimer: This article first appeared on Bloomberg, and is published by special syndication arrangement