The SARS-CoV-2 variant first identified in India last year, called B.1.617, has already become the dominant version of the virus in some parts of the country and could be a driver, among others, of the current outbreak. And it’s one reason countries are now imposing travel restrictions on flights from India. Other variants have already arisen independently in different parts of the world and have rapidly gained ground, too. The World Health Organization (WHO) is now tracking 10 SARS-CoV-2 variants internationally.

It may be hard to grasp the current scale of the pandemic from the US, which has so far managed to fully vaccinate at least one-third of its population while seeing precipitous drops in new cases, hospitalizations, and deaths. All three of the vaccines that have begun distribution in the US have proven to be highly effective at preventing hospitalizations and deaths from Covid-19, the worst consequences of the disease.

However, the US can’t afford to be complacent. Several of these more dangerous variants have already arrived in the US. The Centers for Disease Control and Prevention (CDC) released new Covid-19 models and found that variants are poised to drive an increase in new cases in May.

The challenge now is to vaccinate people to contain the spread of the virus, not just in the US but around the world. As long as the virus is spreading anywhere, it can mutate in threatening ways. But variants aren’t the only factor at play; public health measures and political will to contain the disease will also shape the remainder of the pandemic. How these factors are converging can be confusing, so here are nine questions and answers that may clarify some of the concerns:

1) What is a variant?

Viruses mutate all the time, making mistakes in copying their genetic code as they replicate. Most of these mistakes are actually detrimental to the virus or have no effect. But in rare cases, a change in the genetic code can occur that confers an advantage to the pathogen, alters how it functions, or makes it harder to counter.

The term “variant” refers to a virus strain with a distinct grouping of mutations. Sometimes these variants contain dozens of individual mutations compared to the original strain of a virus. The combination of mutations in these variants may even be working together, making the variants more dangerous than versions of the virus with individual mutations.

Variants of SARS-CoV-2 have arisen at several points during the pandemic, but what’s concerning about the variants spreading right now is that they seem to be better able to spread. Some also seem to lead to more severe outcomes from Covid-19. And several variants seem to be better able to evade the immune system in people who were already infected or in people who have been vaccinated. So variants can increase the chances of a Covid-19 survivor getting reinfected or raise the likelihood of a breakthrough infection in someone who received a vaccine.

2) Why did variants show up all of a sudden?

There are several factors behind why so many SARS-CoV-2 variants have emerged. One is simply that the virus has been spreading to more people in more countries. With more infections, there are more mutations, thereby creating a greater likelihood of a rare combination of those mutations converging in a way that poses a threat.

Selection pressure is playing a role, too. As more people gain immunity through infection or vaccination, the variants that can evade that immunity remain and can circulate.

“It is not an accident that these variants first arose in areas that have a record of poor implementation of measures to mitigate spread and very high rate of infection,” said Theodora Hatziioannou, a research associate professor of retrovirology at the Rockefeller University, in an email. Places like the United Kingdom, for instance, saw major spikes in Covid-19 earlier in the pandemic and struggled to impose lockdowns, creating plenty of opportunities for mutations and the eventual B.1.1.7 variant that was first detected there.

Another factor is that many parts of the world are doing more genetic surveillance of Covid-19. Rather than just detecting the presence of the virus, this work involves sequencing the genome of the virus. It can reveal which specific variant is in circulation in a given area and can detect new mutations as they arise. But in many parts of the world, surveillance is inadequate or nonexistent, which means other variants could be spreading undetected.

3) Which Covid-19 variants are the most concerning?

SARS-CoV-2 variants are grouped into three categories. A variant of interest is one that contains mutations known to affect how the SARS-CoV-2 virus binds to human cells. It could lower the efficacy of Covid-19 treatments or render prior immunity less potent. A variant of concern is one that has shown evidence of causing more severe disease or greater transmissibility, or leads to a significant reduction in protection against Covid-19 stemming from prior infections or vaccination. And if existing Covid-19 countermeasures like testing or vaccines are significantly weaker against a variant, it is labeled a variant of high consequence.

The WHO reported on May 3 that it now has seven variants of interest and three variants of concern on its radar.

The variants all have clunky names, and scientists generally try to avoid identifying them based on where they were first detected, though this often happens anyway. The WHO discourages identifying diseases and variants by location because it can be stigmatizing as well as misleading since where a disease is first detected isn’t necessarily where it originated.

One of the main variants of concern for the WHO is known as B.1.1.7. It was first detected in the United Kingdom last year and has since spread around the world and is poised to become the dominant variant in the US. It appears to be more transmissible, hence its rapid spread, and it appears to lead to more hospitalizations and fatalities, hence the concern.

The B.1.351 variant, first identified in South Africa, also seems to be more transmissible. Similarly, the P.1 variant that was initially reported in Brazil is likely to spread more readily among people. Covid-19 treatments like monoclonal antibodies also seem to be less effective against it.

The CDC has its own variant list focused on the US and includes B.1.427 and B.1.429, both first found in California, on its concern list.

But places like the US and Israel are seeing declines in the rate of new Covid-19 cases, hospitalizations, and deaths despite the presence of variants. That’s due in large to part their success in administering Covid-19 vaccines, though factors like warmer weather may also be reducing opportunities for transmission at the moment. It shows that even if a variant is more transmissible, it can be contained with widespread immunization and good public health practices.

4) How do Covid-19 variants work? What makes them so dangerous?

What ties these variants together is that they contain mutations in SARS-CoV-2’s spike protein, the part of the virus that allows it to infect human cells. Several variants actually have some mutations in common, particularly in the receptor-binding domain of the spike protein. The receptor-binding domain comes into direct contact with human cells and commences the infection process. The mutations in this region seem to enhance the affinity of the virus for human cells, which may allow it to reproduce more.

One of the most concerning mutations in this region is known as E484K, where the amino acid glutamate is replaced by the amino acid lysine at position 484 in the spike protein. It has been found in several variants, including B.1.525, P.1, B.1.351, and some strains of B.1.1.7. It is also known to be an escape mutation because it can help the virus evade the immune system’s defenses. That means variants with this mutation might be more likely to reinfect people who have already had Covid-19.

Similarly, the N501Y mutation in the receptor binding domain has also been identified in variants like P.1, B.1.1.7, and B.1.351. It too enhances transmission.

There are also mutations outside of the receptor binding domain that can change the overall shape of the spike protein in a way that makes it more efficient at invading cells or make it a tougher target for the immune system.

However, scientists are still working to confirm exactly how these variants function and how these mutations may be working in concert.

5) Are Covid-19 variants driving the devastation in India?

The number of daily new infections in India has not dipped below 300,000 over the past two weeks, and that is likely an undercount given the difficulties of testing for the virus and limited access to health care for many Indians. Some estimates show the actual case counts could be 10 times higher. The cases are driving shortages of hospital space, personnel, protective equipment, oxygen, and even crematorium capacity. Yet the Indian government remains reluctant to impose new restrictions on movement and public gatherings.

One of the factors at play is a SARS-CoV-2 variant known as B.1.617 that was first identified in India in October 2020 and has since been found in at least 17 countries, including the US. It’s been described as a “double mutant,” which isn’t technically accurate because it contains many different mutations. But it does contain two mutations that have been observed in other strains to increase transmissibility and evade some of the immune protection some people have from previous Covid-19 infections.

B.1.617 has already become the dominant variant in several Indian states. The situation echoes the P.1 variant outbreak in Brazil. In January, that variant spread rapidly in the city of Manaus, which had already faced a major Covid-19 outbreak in October 2020 that led to more than three-quarters of the population getting infected, according to some estimates.

The cause of Brazil’s second wave isn’t certain, but it may have been due to a combination of immunity waning from the first wave coupled with a variant that’s more transmissible, allowing for reinfections.

A similar situation may be occurring in India with the B.1.617 variant, but the evidence isn’t clear yet that it’s the main culprit behind the massive surge in infections. India is also coping with the B.1.1.7 and B.1.351 variants.

And both Brazil and India have made critical missteps in their public health responses to Covid-19. Brazilian President Jair Bolsonaro routinely dismissed the severity of Covid-19 and is now facing an investigation from Brazil’s Senate over his mishandling of the pandemic.

Indian Prime Minister Narendra Modi’s political party declared that the country had “defeated” Covid-19 back in February. Restrictions on public gatherings were lifted, major religious festivals took place, and political rallies continued. “I think that there was complacency here,” said Amesh Adalja, a senior scholar at the Johns Hopkins Center for Health Security.

And although India is the world’s largest vaccine manufacturer, Covid-19 vaccination rates in its population remain low, leaving hundreds of millions vulnerable to infection. More than 150 million shots have already been administered in India, but some analysts warn vaccinating all eligible adults in the country could take years. The main vaccines being administered are the University of Oxford/AstraZeneca vaccine, known in India as Covishield, and the Covaxin vaccine made by Indian pharmaceutical firm Bharat Biotech. Russia’s Sputnik V vaccine was also recently approved in India, with injections arriving last week. All of these are two-dose vaccines and seem to retain protection against the variants circulating in India.

It may be that the combination of the more transmissible B.1.617 variant, relaxing restrictions too soon, and a low vaccination rate are all fueling the Covid-19 devastation in India. This surge in cases has global implications since India’s vaccine production is critical to vaccinating other countries.

If the virus continues to spread unchecked, it will increase the chances of another dangerous variant emerging. And other countries that have similarly low vaccination rates and poor public health responses could experience major increases in cases in the coming months.

6) Do Covid-19 treatments still work against the variants?

There are a variety of treatments now available for Covid-19 that have helped reduce the severity and lethality of the disease.

However, some of the more targeted treatments, like monoclonal antibodies, seem to be less effective against several of the Covid-19 variants, like B.1.351 and P.1.

Antibodies are proteins produced by the immune system that can attach directly to a specific part of the virus, inhibiting its function or marking it as a target for white blood cells to eliminate. Monoclonal antibody therapies — like the ones from Regeneron and Eli Lilly — harness and clone a single antibody that is known to be highly effective at binding to its target (Regeneron’s drug uses a cocktail of two monoclonal antibodies).

In the case of Covid-19, the target for these drugs is the spike protein of the virus. But if the spike protein mutates in the spot that the antibodies target, then these drugs could become less effective. In April, the Food and Drug Administration (FDA) revoked its emergency use authorization for the monoclonal antibody therapy developed by Eli Lilly when used alone because several of the new Covid-19 variants seem to be resistant to it. Combinations of two or more antibodies still appear to be effective, possibly because the antibodies target different parts of the spike protein and it’s less likely for both locations to have mutations.

On the other hand, more general treatments for Covid-19 are not likely to be affected by the variants. Corticosteroids like dexamethasone tamp down on the immune system’s overreaction to the virus rather than targeting the virus itself, so mutations likely won’t have a major impact. Remdesivir, an antiviral drug and the only one with full FDA approval to treat Covid-19, seems to be just as effective against the new variants as it is against the original strain, but there remain questions about how effective the drug was to begin with.

7) Will vaccines still protect you against the variants?

For now, the main Covid-19 vaccines being distributed across the US — from Moderna, Johnson & Johnson, and Pfizer/BioNTech — remain highly effective at preventing illness, hospitalizations, and deaths, even from the new variants reported so far.

“It is true that there is less efficacy against these new variants, but it doesn’t mean there is a complete absence of protection,” said Fikadu Tafesse, an assistant professor at Oregon Health & Science University. “The good thing is these vaccines are extremely good.”

One of the main exceptions, however, is the University of Oxford/AstraZeneca vaccine. It failed to hold up well against the B.1.351 variant that’s become predominant in South Africa. It performed so poorly in trials that South Africa decided to halt the use of the vaccine and is now selling its supply to other countries. This vaccine has not yet been approved for use in the US but is still being administered in other countries where B.1.351 is not in widespread circulation.

On the other hand, even the best vaccines are not a perfect defense. Health officials have observed a number of “breakthrough” cases where people still managed to contract Covid-19 after being vaccinated. However, the breakthrough rate is much, much lower among vaccine recipients than the infection rate among unvaccinated people.

And among the breakthrough cases, the illness was much less severe, with most patients reporting mild or no symptoms. This shows that Covid-19 vaccines not only prevent illness but make the illnesses that do occur much less dangerous, downgrading the disease from a life-threatening malady to a minor annoyance for most people.

“We have to change our definition of Covid-19 experience [away] from being infected,” said Larry Luchsinger, vice president and director of research operations at the Lindsley F. Kimball Research Institute at the New York Blood Center. “The conversation has to change back to ‘how severe was your reaction.’”

8) Will we need new vaccines or boosters to protect against variants?

Given that most Covid-19 vaccines remain strong against variants, it’s not clear yet whether we will need booster doses for vaccines or if vaccines will need to be reformulated. For example, a recent study just found that the Pfizer/BioNTech Covid-19 vaccine is still effective against the B.1.1.7 and B.1.351 variants, albeit with reduced efficacy.

That could change as more variants arise or if it turns out that immunity to Covid-19 declines faster than the rate of the virus in circulation. And the approach may be different depending on whether someone received a vaccine or gained immunity from a prior infection.

“Recent evidence suggests that, at least for people that had been previously naturally infected, vaccination confers a high level of neutralizing antibodies that can neutralize even the variants of concern,” Hatziioannou said. “This to me suggests that repeated exposure to the antigen could be potentially advantageous and I would be in favor of booster shots.”

Part of the challenge is that Covid-19 has only been around for just over a year, so scientists don’t have a good handle on how long immunity will last from a vaccine or from a previous infection. Experiences with past coronaviruses do show that immunity can last for several years. If the Covid-19 pandemic is sufficiently controlled before immunity fades, boosters may not be necessary.

An advantage of several of the Covid-19 vaccines is that they can be easily and quickly modified. The Moderna vaccine and the Pfizer/BioNTech vaccine are based on a molecule called mRNA. It carries instructions for making the spike protein of SARS-CoV-2. The Johnson & Johnson vaccine and the Oxford/AstraZeneca vaccine use a modified adenovirus to carry DNA that codes for the SARS-CoV-2 spike protein.

Human cells read that DNA or mRNA genetic information and make the spike protein. The immune system then detects the spike protein and starts to mount a response. To modify these vaccines, one only needs to alter the genetic instructions, which can be done within days.

Vaccine manufacturers are currently studying booster doses — an extra dose of the same vaccine — as well as reformulated vaccines to target specific variants. Moderna, for instance, has already reported early results that show its modified vaccine neutralizes the P.1 and B.1.351 variants. For its part, the FDA has also cleared the way to deploy new formulations of Covid-19 vaccines so that they don’t have to go through the same tedious and expensive clinical trials process to get approval. Instead, the modified vaccines will go through a more condensed testing regimen akin to annual influenza vaccines, allowing them to be deployed faster.

9) Will variants thwart our attempts to return to normal?

Only if we let them.

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Vaccination remains the most powerful way to corral Covid-19, but it’s only one component in a suite of public health tactics. Until the vast majority of people are immune, wearing face masks, proper ventilation, and social distancing will also be needed, depending on the specific situation. Genetic surveillance is also critical to staying ahead of the variants.

The goal is to get enough of the population immune to Covid-19 such that the virus can’t spread easily. That threshold is known as herd immunity, and for Covid-19, it may take between 70 and 80 percent of the population to become immune. And vaccination helps ensure that if cases do occur, they remain mild and there is adequate capacity in the health system to deal with them.

However, herd immunity isn’t a fixed line. It can change depending on the particular variant in circulation and the susceptibility of the population. And it can change from place to place depending on the level of immunity in a given region.

Right now, the US is shifting away from vaccinating the willing to vaccinating those that may be more reluctant. Immunizing those holdouts may end up being the critical factor in drawing down the pandemic. But if they remain vulnerable, that could allow the virus to continue to circulate and spawn new outbreaks.

The biggest threat, though, remains the ongoing and unchecked spread of Covid-19 across many parts of the world. These cases are not just an enormous human tragedy but the surge in infections threatens to undermine precious gains against the disease.

And the current pace of vaccination is alarmingly low. Estimates show that it will take until 2023 to vaccinate some countries against Covid-19. If the pandemic drags on that long, the whole world will remain at risk. As economies reopen and international travel picks back up, controlling the spread of Covid-19 in other countries will become even more important as the chances of another variant spreading will increase. That’s why ending the crisis as we know it demands a global lens, with a coordinated international effort to vaccinate the world and to reach the most vulnerable.