Imagine taking all the virus particles from someone infected with SARS-CoV-2. If you were to sequence them, you'd find that the virus particles are not all identical. That's because when viruses make copies of themselves, they make mistakes. Most of these go completely unnoticed, because they don't confer any advantage to the virus, or maybe even make it less competent at reproducing. But given how much the virus has spread around the globe, SARS-CoV-2 has had a lot of opportunity to mutate.
Gigi Kwik Gronvall, PhD: A lot of viral evolution just comes down to statistics. A particular mutation may confer the ability of the virus to make more copies of itself or to be more sticky to cells or whatever it is. And then over time, you'll see that it becomes more predominant in the population, because of that selective advantage that it has.
And this is exactly what has happened with the variants being detected around the globe. These variants are often referred to by the location where they were first detected--like California, South Africa, etc.--but they are widespread. For instance the variants first detected in the UK, South Africa, and Brazil are already circulating in the US.
This is concerning for many reasons, but one of the biggest questions is whether these variants will dampen the effectiveness of available vaccines. So what does the available data tell us, and what should you pay attention to as this situation develops?
When researchers talk about vaccine efficacy, a lot of attention is paid to antibodies, specifically neutralizing antibodies. The leading COVID-19 vaccines all induce neutralizing antibodies, which bind to the virus at a few different sites on the spike protein, called epitopes. This literally blocks the virus from attaching to cells.
The mutations that are most worrisome in terms of vaccines are those that affect neutralizing antibody binding sites on the spike. So the first step in understanding how a variant will impact vaccine effectiveness is to analyze where the mutations are. But while this provides important clues, it doesn't give you the full picture. So let's take a look at some of the other data that researchers pay attention to.
[Testing variants against vaccine serum]
Serum is the liquid component of blood that contains antibodies. You can take the serum of someone who has been vaccinated and combine that with the virus, in the lab, to see if the antibodies contained in the serum block the virus from infecting cells.
Adam S. Lauring, MD, PhD: And so what we see is a lot of studies where you take serum, you test it with virus one, virus two, and see if there's a difference. And that provides you a clue of whether the antibodies that are stimulated by the vaccine protect you or not.
There is currently no centralized system for testing all the different vaccine sera against all the different variants. Most studies have been small, and have primarily focused on the two mRNA vaccines from Moderna and Pfizer.
Let's start with the B.1.1.7 variant first detected in the UK. Modeling suggests that this variant is likely to become predominant in the US. Luckily, serum testing indicates that antibodies induced by the two mRNA vaccines remain effective.
John P. Moore, PhD: So that is not an escape mutant. It's not an antibody-resistant virus, and I can't imagine it would be a significant reduction in vaccine efficacy for Pfizer and Moderna.
But for the B.1.351 variant first detected in South Africa, serum testing points to a reduction of about six-fold in antibody sensitivity.
John P. Moore, PhD: But that's not a catastrophe. That's a sort of eyebrow-raising ground for concern, but not a freak out situation. Because the strong antibody responses to the two doses of Pfizer and Moderna should be able to cope with this. So if you reduce from a strong position, you still have a reasonably strong position.
Essentially, because the two mRNA vaccines were so strong to begin with, there is more of a cushion. This wouldn't be the case if the vaccines had started out at a much lower efficacy.
The other variants of concern currently identified by the CDC are P.1, which was first detected in travelers from Brazil, and two variants first detected in California, B.1.427 and B.1.429. Fewer studies are available on these variants, but current data indicate that the reduction in antibody sensitivity is somewhere in-between B.1.1.7 and B.1.351.
Overall, we need more laboratory data. But even when larger studies become available on all the different variants and vaccine sera, these data may prove inconclusive. Testing against serum samples has limitations. A big one is that antibodies are only one part of the immune response.
Adam S. Lauring, MD, PhD: You know, in serum, you won't have your T cells, you won't even have your memory B cells or plasma cells that might, you know, be important, just for the antibody response. So, there's a lot we're missing.
And that makes it hard to determine how a decrease in antibody sensitivity of, say, 6-fold, in the lab, translates to vaccine effectiveness in the real world. Given these limitations to laboratory testing, it is of paramount importance to collect data on the ground.
One example of such data would be sequencing the variants infecting people who become seriously ill with COVID-19 despite being vaccinated.
Paul A. Offit, MD: Here's the way I see this. Here's when you should worry. You should worry when people who have been either naturally infected or have completed their immunization series are nonetheless hospitalized with one of these variants. That tells you I think that an important line has been crossed. That hasn't happened yet.
Another source of on-the-ground data is ongoing and recently-completed vaccine clinical trials.
[Data from clinical trials]
The AstraZeneca vaccine did not fare well in South Africa, where the B.1.351 variant is dominant, and South Africa halted its distribution in February. AstraZeneca is getting close to filing for authorization in the US, and this vaccine is already being distributed elsewhere, including in the UK, Europe, and by the World Health Organization.
Another vaccine that was tested in South Africa is from Novavax. This vaccine is not yet being distributed, but it is getting close to filing for authorization in the UK, US, and elsewhere. The most recent press release read-out of data suggests that while the Novavax vaccine was almost 90% effective in the UK, it was much less effective in South Africa--about 49 or 55% depending on whether or not you include participants infected with HIV.
Data from Johnson & Johnson vaccine, which is now being distributed in the US, reports a similar trend. The J&J vaccine was 72% effective at preventing moderate to severe disease in the US 28 days after vaccination. In South Africa, that number was only 64%. But, importantly, the J&J vaccine efficacy against severe disease was similarly high across all regions.
Paul A. Offit, MD: So that's good news. I mean, that's what you want. You just want this vaccine to keep you out of the hospital, keep you out of the ICU, and keep you from dying. And right now, that all appears to be true. I mean, you're making a polyclonal antibody response against a variety of epitopes on that virus. And right now, that response appears to be good enough to protect you from severe disease.
So the currently-available data indicate that while variants do pose a real threat to vaccine effectiveness, the available vaccines remain potent tools in fighting the pandemic. But researchers and public health experts also stress that there will be more SARS-CoV-2 variants. And this underscores the importance of a global approach to surveillance, tracking, and vaccine deployment.
The US had been lagging in terms of the proportion of virus load around the country that gets sequenced. But CDC Director Dr Rochelle Walensky has emphasized the need to scale up surveillance across the US.
Rochelle P. Walensky, MD, MPH: I think, in early January, there was 250 samples a week that were being sequenced. We're now in the thousands. We're not where we need to be. It's not, I think I said earlier, it's going to be a dial, not a switch. And we're going to need to dial it up.
In addition, the CDC, NIH, vaccine producers, and other groups are already discussing and collecting data on various vaccine strategies for combatting variants. One potential strategy is a booster shot that would expose your body to the viral spike protein from the newer, resistant variant. This would stimulate the immune system to produce antibodies specific to that new variant. Another strategy is a booster shot of an already-authorized vaccine. So in the US, this would be a third shot of the Pfizer or Moderna vaccine, or a second shot of the Johnson & Johnson vaccine. An extra dose would boost the amount of antibodies to the wild-type virus, and that extra cushion should carry over to protection against variants also.
Studies evaluating both booster approaches have already started. Other strategies may also be on the horizon, like bivalent vaccines, which induce an immune response to two different antigens with one shot. Such a vaccine could induce immunity to two different variants; or to two viral proteins from the same variant. But while such strategies are important to evaluate, the most significant way to mitigate the threat posed by variants is to reduce the community spread of SARS-CoV-2.
Rochelle P. Walensky, MD, MPH: We all know that the more viruses replicate they more they mutate. The more they mutate, the more we're likely to see dominant variants that could really emerge and become a problem for us. So the best thing that we can do to prevent these, in general, is to have less disease circulating, less virus circulating.
And the way to decrease the amount of virus circulating is to get as many people vaccinated as possible, as quickly as possible, and to continue preventive measures like mask wearing and physical distancing. So while a lot needs to happen at the level of scientific institutions and governments, of no less importance is continued adherence to basic public health measures on the part of every individual around the globe.