Covid-19 vaccines: How Moderna, Pfizer/BioNTech, and Johnson & Johnson are preparing for variants

The world is now locked in an arms race with Covid-19, as multiple effective vaccines are being deployed (at staggeringly different rates) around the world. At the same time, new variants of the SARS-CoV-2 virus have been rapidly spreading.

The Covid-19 vaccines that are being distributed in the US, as well as the newly authorized Johnson & Johnson vaccine, have been shown to almost eliminate deaths and hospitalizations from the disease, even for people infected with the new mutations. For a disease that has infected more than 114 million people around the world in just over a year, this is tremendously good news.

But it’s no time to kick back.

There’s evidence that the virus is evolving in ways that can reduce the effectiveness of Covid-19 vaccines — particularly when they’re up against the variant discovered in South Africa. Both Johnson & Johnson and Novavax’s vaccine efficacy rate dropped in the South Africa arm of their clinical trials (from 72 in the US to 64 percent in South Africa and from 89 in the UK to 49 percent, respectively).

The vaccines still worked against their new foe in the majority of trial participants. The human immune response, after all, is robust and multi-layered. It can adapt to different versions of the virus that come along, which is why vaccine-induced immunity is unlikely to “fall off a cliff and go from 95 percent to zero,” as University of Utah evolutionary virologist Stephen Goldstein told Vox.

However, the situation is still dicey. “Eventually, when the majority of the susceptible population is vaccinated with effective vaccines, the variant better suited for survival in the new host will be one that has the ability to evade the vaccine-induced immunity,” researchers warned in a March 1 letter published in Nature. Such a variant could “decrease, and even abolish, the beneficial effects of a broad immunization program.”

And the more people the virus infects, the more mutations it acquires — mutations that may eventually evade the protection provided by prior infections or from vaccinations. The slow pace of the global vaccine rollout, particularly in low- and middle-income countries, then means that even if people in rich countries like the US are fully vaccinated, variants may still emerge in less vaccinated regions, increasing the risk of new outbreaks everywhere.

That’s why, while global health groups work to get more vaccines to more people around the world, vaccine developers are quickly trying to find new strategies to cope with the variants. They’ve already brought new vaccines to the market in record time. Now they are investigating everything from booster shots to entirely reformulated vaccines.

What we know about the coronavirus variants and Covid-19 vaccines

All viruses mutate as they move through populations, and until recently, the mutations in SARS-CoV-2 weren’t cause for much concern. (A mutation is a change in the genetic makeup of a virus, while a variant is a virus that has a suite of mutations that alter how it behaves.) That changed in mid-December, when a more contagious variant known as B.1.1.7 was discovered in Britain, just as the first Covid-19 vaccines were coming online.

That was only the beginning of a new chapter in the pandemic. Since then, several new variants and mutations of concern — what the WHO calls changes to the virus that are worrisome — have surfaced in dozens of countries around the world, becoming the dominant strain in some.

The Centers for Disease Control and Prevention predicted that B.1.1.7 could overtake other versions of the virus in the US this month. And evidence is mounting that B.1.1.7 is not only more transmissible but potentially also deadlier than prior versions of the virus.

Another variant, B.1.351, first identified in South Africa, has proven more difficult to immunize against. And still another immune-evading variant discovered in Brazil, known as P1, has already spread to at least 25 other countries, including the US. Scientists reported that in several instances, the P1 variant was behind reinfections in people who already survived an earlier course of the illness. And two new variants may have emerged in the United States, in New York and in California. These new variants of concern stand to undermine precious progress against the pandemic because they’re either more contagious, potentially more dangerous, or threaten the vaccines we have. And perhaps even more ominously, they’re a reminder that far more — and perhaps even more threatening — variants will emerge in the future.

Adding to the threat is that many parts of the world, including the US, are not doing enough genetic sequencing of SARS-CoV-2. That makes it harder to identify and prepare for new variants when they emerge, increasing the chances of them spreading undetected.

The good news is that, for the most part, vaccines still seem to provide good protection against the SARS-CoV-2 variants discovered so far. So does prior infection.

But there have been some worrying signs that current Covid-19 vaccines are less effective against some new variants — again, B.1.351, first identified in South Africa.

How can seemingly minor mutations change the virus’s susceptibility to a vaccine? When a vaccine is administered, the human immune system responds by producing targeted antibodies, proteins that can stick to a specific pathogen. Antibodies that prevent that pathogen from causing an infection are said to be neutralizing.

Studies show that the vaccines developed by Pfizer/BioNTech and by AstraZeneca/Oxford lead to a lower concentration of neutralizing antibodies to B.1.351 than to the older versions of the virus, explained Benhur Lee, a professor of microbiology at the Icahn School of Medicine at Mount Sinai. However, these vaccines generate such a high level of neutralizing antibodies to begin with that the reduced protection is still effective.

Antibodies are also just one component of the immune response. A recent preprint found that immune protection provided by T cells generated in response to a Covid-19 vaccine was just as potent against the new variants.

“This is probably the reason why you see other vaccines still being efficacious in South Africa,” Lee said in an email. So a drop in efficacy doesn’t mean the vaccines are rendered useless, but it does mean they’ll be less protective in environments where variants like B.1.351 are spreading.

In South Africa, the AstraZeneca/Oxford vaccine, which has not been approved in the US, has been pulled from the country’s vaccination campaign. Officials found that it was less effective against the new variant, but the findings came from a small trial of roughly 2,000 people. “Since they had the option of Pfizer and J&J coming down the line, South Africa chose to go ahead with those other vaccines,” Lee said.

The vaccines may also provide less resistance to milder forms of Covid-19 spawned by the new variants. Even if they don’t land someone in the hospital, such infections can still reduce quality of life, especially for people with other preexisting health conditions. And we’ve already seen that even seemingly mild cases of the disease can have lasting effects: persistent fatigue, brain fog, and so on.

Another public health concern with regard to vaccines is how well they block transmission of the virus. This is a crucial factor in controlling the pandemic in the population, particularly when vaccination rates are still so far away from reaching herd immunity.

For now, there is less information about how well vaccines block transmission than there is when it comes to stopping the disease in people. Identifying infections, particularly asymptomatic cases, requires aggressive testing for the virus within a study, an expensive and time-consuming task. But the research that is emerging so far is encouraging.

A recent preprint study from the UK reported that the full course of Pfizer/BioNTech vaccine reduced the chances of developing a transmissible infection by 86 percent. Another preprint study, looking at Covid-19 vaccines in Israel, saw an 89.4 percent drop in transmissible infections.

Will the variants also erode protection against transmission?

It’s possible, but there’s little research to date. The variants already seem to cause more cases of disease with symptoms — early evidence about B.1.1.7 suggests this is the case — so it’s likely that infected people may generate and shed more virus, helping it spread. If SARS-CoV-2 variants lead to more infections breaking through the protection barrier of vaccines, those infections in turn could spur further transmission.

But as with the vaccine protection for individuals, a barrier to transmission, even if it’s lower, would still slow the spread of the virus within a community.

“Even a less efficacious vaccine will be an important tool to tamp down a highly transmissible strain,” Lee said.

How Covid-19 vaccine manufacturers are preparing for the variants

One advantage that we have in this race against the variants is that the new vaccines being rolled out around the world so far are also very nimble.

The Pfizer/BioNTech vaccine and the Moderna vaccine both use a molecule called mRNA as their platform. This molecule delivers instructions to the body to make a spike protein found on the SARS-CoV-2 virus, educating the immune system to fend it off if it encounters the actual virus in the future.

Meanwhile, the vaccine developed by the University of Oxford and AstraZeneca that recently received approval in the UK (but not yet in the US) uses a reprogrammed version of another virus, an adenovirus, to shuttle DNA that codes for the SARS-CoV-2 spike protein to use as target practice. The one-dose Johnson & Johnson vaccine that recently received an emergency use authorization from the FDA also uses an adenovirus vector.

In both of these fairly new vaccine platforms, developers only need to modify the code of DNA or mRNA to tweak the vaccine to reorient it to new variants, something they can do quickly if necessary.

But while it may be possible to alter the vaccine to adapt to new mutations, it’s not ideal: It requires expensive changes in the vaccine production process and eats up valuable time.

“It takes time to manufacture hundreds of millions of doses,” Lee said.

Another approach is to build off of existing vaccine formulations but add on another shot. For example, companies like Pfizer are considering adding a third, booster dose to their two-dose Covid-19 vaccine regimen to solidify the response to the new variants. “We believe that the third dose will raise the antibody response 10- to 20-fold,” Pfizer CEO Albert Bourla told NBC News on February 25.

In an email, a Pfizer spokesperson explained that the company hasn’t seen a loss of protection against the new variants in its laboratory studies, but is proactively gaming out several responses, like a booster dose, through further clinical trials. “We need to focus both on vaccinating the world with an initial regimen and be driven by the science of our clinical studies for the boost,” according to the spokesperson. “We are focused on enrolling the full study and should have the findings soon.”

Moderna, meanwhile, announced on February 24 that it has sent a version of its vaccine optimized to handle the South Africa variant to the National Institutes of Health for further study. The company is also investigating a booster dose.

Johnson & Johnson’s phase 3 clinical trial commenced after those from other manufacturers, so they were able to capture the efficacy of their vaccine against some of the new variants. “The [Johnson & Johnson] Covid-19 vaccine candidate also provided protection against multiple Covid-19 variants,” according to a spokesperson for the company. Johnson & Johnson is also studying a two-dose version of its vaccine.

For its part, the FDA announced it is streamlining the approval process for vaccines to target the new SARS-CoV-2 variants, making the procedure similar to approvals for annual influenza vaccines.

“If Covid-19 becomes an endemic, potentially seasonal virus, we can establish a regulatory pathway that will allow us to move expeditiously to update and validate an updated vaccine, similar to what is done with the flu every year,” said a Pfizer spokesperson.

However, researchers say one shouldn’t hold out for a reformulated vaccine and should take the first shot they’re offered. Whether a vaccine manufacturer opts for a booster, a reformulation, or decides to stick with the existing protocol, timing is critical, and people need to be vaccinated as fast as possible to contain the pandemic.

What do variants and vaccines mean for how the pandemic ends?

There are at least several possibilities for how the pandemic will fade away. Covid-19 could become a largely intermittent threat, with sporadic outbreaks. It could also become seasonal, with surges in the fall and winter. These possibilities make the evolution of the pandemic in 2021 even less predictable than 2020.

“The question mark is going to be next fall, next winter. Is there going to be a new variant that becomes dominant again? Are we going to see efficacy from the vaccines start to wane by that time?” said Anish Mehta, medical director for clinical quality and virtual health at Eden Health, and a professor of medicine at the Icahn School of Medicine at Mount Sinai. “That’s what’s really going to be the big test for us.”

One thing we do know is that the suite of public health strategies used so far — social distancing, hand-washing, mask-wearing — remain useful. “A lot of the things that we’ve been doing throughout this pandemic will continue to work when it comes to these variants,” said Gigi Gronvall, a senior scholar at the Johns Hopkins Center for Health Security, during a press call.

If vaccination rates continue rising while new infections decline, the United States may be able to stay ahead of the virus. Life could return to something approaching normal for most Americans by this summer, according to Mehta.

But it’s turning out that many parts of the world, especially developing countries, aren’t able to keep up. There are places that still aren’t able to get vaccines at all — and probably won’t for a couple of years. As SARS-CoV-2 continues to spread, the likelihood of even more mutations arising will increase. And as has already been demonstrated, new variants don’t stay behind borders for long.

That’s part of why it’s so important to work toward equity in Covid-19 vaccine distribution around the world. As long as the virus can spread anywhere, it’s a threat everywhere.

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