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India is undergoing a massive vaccination effort in the midst of a devastating rise in reported daily cases and deaths. While the main cause of the rise in cases is yet to be determined, epidemiological and virological data point to the rise of new variants of concern being a major contributing factor.

This year, we have been hearing about how many variants of concern of SARS-CoV-2, the coronavirus that causes covid-19, have arisen through mutations. We have also been hearing about how some of these variants, including B.1351 (first identified in South Africa), P.1 (identified in Brazil), and B.1.617 (identified in India and referred to as “double mutant"), are spreading and leading to immune escape.

In the midst of these variant discoveries, there are conflicting reports on vaccine efficacy. So, here’s a summary based on science of what we currently know, what we don’t know, and what we can infer. Let’s start by asking what exactly is “immune escape"? Should we worry about it? And what does it mean for those who are already vaccinated?

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Variants of concerns are mutated forms of SARS-CoV-2 that are more infectious, can cause more severe disease, can evade some immune responses, or do any combination of the above. Immune escape variants have mutations that prevent them from being tagged by antibodies, generated either because of prior infection or due to vaccination.

Effective neutralizing antibodies can stick to specific parts of the spike protein on the virus, preventing it from attaching to the receptor on the cell. Therefore, antibodies have a major role to play in preventing infection, both after natural infection and vaccination.

Viruses naturally mutate. Over time, those mutations that help the virus to escape from the antibodies can be maintained since they confer a selective advantage.

Because vaccines were not developed with variants in mind, the antibodies that result from the first generation of covid-19 vaccines might not be able to neutralize variants in similar numbers to earlier versions of SARS-CoV-2.

While there is much to learn about emerging variants and how vaccines work against them, there is already much that we know. Headlines on “immune escape" variants may indeed be alarming, but they are also simplistic. The immune system is analogous to a complex machine with many parts and settings. It isn’t a switch that goes between “on" and “off".

The variant first identified in the UK (B.1.1.7) has been shown to be more infectious than the dominant strain of SARS-CoV-2 prevalent in 2020. There are fewer antibodies that recognize B.1.1.7 after vaccination compared to the ancestral virus. However, it is not an “escape mutant" because there are still enough antibodies for vaccines to remain very effective compared to clinical trials.

Vaccines that have been tested are less effective in producing neutralizing antibodies against the P.1. (first identified in Brazil) variant. But of all the variants studied to date, the most concerning in terms of reduced vaccine protection is B.1351 (identified in South Africa).

At the time of writing, we know significantly less about B.1.617, but can get a sense of what might be happening by looking at mutations in this variant. B.1.617 has erroneously been called a “double mutant", when in fact it has 15 mutations that result in changes to its amino acid building blocks.

One of the mutations is in the 484 position of the spike. This mutation results in a drop in the neutralizing ability of those who have had natural infection with SARS-CoV-2 in the past. Another mutation at the 452 position has been seen in variants identified in California and results in weaker neutralization.

Taken together, we can predict that the reduction in antibodies on exposure to the variant B.1.617 after vaccination is likely somewhere between B.1.1.7 and B.1.351. More experimental data is needed to confirm this inference.

The research

The best way to examine the effect of variants on vaccine efficacy is in a well-designed clinical trial. Clinical trials undertaken in South Africa with Johnson & Johnson and Novavax vaccines have reported lower efficacy for symptomatic covid-19 compared to other locations where this variant is less prevalent.

But one encouraging aspect of the trials with the Johnson & Johnson vaccine was that the efficacy against severe covid-19 was above 80% in both the United States and South Africa. The most important goal of vaccinations is to keep people out of hospitals and alive and this vaccine seems to be achieving this.

The AstraZeneca vaccine (equivalent to Covishield) did not fare as well in South Africa. A trial of around 2,000 people reported in the New England Journal of Medicine assigned to either vaccine or placebo groups found that the vaccine could not prevent mild to moderate covid-19 to a considerable extent. The trial could not determine if the vaccine prevented severe covid-19 because most of those who were enrolled were young. Even in the absence of vaccination, severe disease is rarer in young populations. Another limitation of the trial is that it was small.

In the absence of clinical trials in people, there are ways to test vaccines against variants in the laboratory. Researchers are currently reporting antibody numbers from test variants to detect possible “immune escape".

Many of these laboratory tests check how well antibodies recognize and prevent variants from attaching to cells. Serum is the fluid component of blood that contains antibodies. It is taken from those who have been vaccinated and is tested against variants.

Some of these tests have demonstrated reduced neutralization in immune escape variants. For example, both AstraZeneca and Novavax vaccines failed to neutralize the B.1351 variant indicating insufficient recognition by antibodies.

But these antibody neutralization tests have limitations because serum doesn’t contain T cells, memory B cells or plasma cells which are other important components of adaptive immunity in addition to antibodies. In short, it is very difficult to recapitulate what is happening in the body from laboratory tests because they don’t capture the entire landscape of human immunity.

In fact, for infections with many other coronaviruses like SARS and MERS, we know that even after antibodies fade naturally months after infection, T cells step in to prevent severe disease. Something similar has been predicted with SARS-CoV-2. T cells might not be able prevent the virus from infecting cells the same way that antibodies do, but they might still play a vital role in reducing the severity of symptoms. T cells are expected to play a major role after vaccination too. Encouragingly, a recent study found that SARS-CoV-2 variants of concern did not significantly alter T cell responses in recovered covid-19 patients or those who had received mRNA vaccines.

The inference

All of the above data—taken together with the clinical data from South Africa on the ability of Johnson & Johnson vaccine to prevent severe disease—are a cause for hope for all vaccines.

Conceptually, it also makes sense. Complete escape from immunity would mean that there would be absolutely no difference in immune responses between vaccinated and unvaccinated populations. Given that vaccines engage various parts of the immune system together, this is extremely unlikely.

In an elegant perspective in the Proceedings of the Royal Society B, published in 2017, David Kennedy and Andrew Read laid out the reasons. Vaccines act early and prepare the host immune system before an attack, and they establish not one but many targets on a virus.

The vaccines that work to prevent covid-19 generate polyclonal antibodies that recognize different parts of the virus, and it is unlikely that all of these parts will rapidly change in emerging variants. In other words, any variant of concern might evade some antibodies in someone who has been vaccinated, but it is less likely to evade all antibodies, T cells, and components of the innate immune system in a way that makes that person completely unprotected.

What is more likely is that certain changes in variants might make some antibodies less capable of neutralization and might shift clinical outcomes in some people. Someone who might not have been infected with the earlier SARS-CoV-2 that emerged in Wuhan after vaccination might have mild or moderate covid-19 disease after exposure to an immune escape variant.

But determining the actual impact will take time. It is difficult because we cannot gauge the drop in effectiveness of vaccines in dealing with variants from just looking at the number of infections. Clinical trials of approved vaccines were not set up to prevent infections as a primary goal. They were designed to see if the vaccines could prevent disease and death.

And right now, we don’t have a baseline number of infections in vaccinated people. We know that some vaccinated people are getting infected regardless of the prevalence of variants in the area. This is why vaccinated individuals have also been advised to wear masks, socially distance, and avoid crowded settings.

The India impact

The key question we have to ask right now is this: with the variants spreading across India, are vulnerable people who have received both doses of approved vaccines getting admitted to hospital ICUs and dying?

So far, encouragingly, there have been no reports of widespread mortality in those who have been exposed to any lineage of SARS-CoV-2 after receiving both doses of any vaccine. This may change over time, but after hundreds of millions of vaccinations, this should be a cause of optimism. Vaccines are indeed saving lives.

The data from multiple studies indicates that we will need to continue monitoring the spread of variants through genomic surveillance, but vaccinations will play an important role in ending the pandemic. They may not prevent infection from certain variants of concern or even stop mild to moderate symptomatic covid-19, but to-date all data indicate that they are extremely effective in preventing severe infections.

In the future, updated booster shots tailored to specific variants could strengthen the immune response to variants. Mixing vaccine types, for example, by giving an mRNA vaccine (Pfizer or Moderna) to someone who has received an adenoviral vector vaccine (Astra Zeneca/Covishield, Sputnik V, or Johnson & Johnson) or vice versa, may be another approach.

There may even be a need for bivalent vaccines that work against two different variants at once. Researchers are looking into different approaches to combat variants right now, but the vaccines we have are powerful tools in reducing the healthcare burden of the pandemic.

To sum up, all vaccines may not work equally well against all variants in preventing covid-19, but if they can keep people alive, they have met a primary objective.

Anirban Mahapatra, a microbiologist by training, is the author of Covid-19: Separating Fact From Fiction. These are his personal views.

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