31
Jan
2021

The Evolving Virus Against the Vaccines

Larry Corey, MD

For about a month, we were lulled into thinking we had turned the corner and were winning the battle against the virus.

With 95% effectiveness in preventing COVID-19 illness and nearly 100% efficacy in preventing severe disease, we just needed to mass produce these wonderful mRNA vaccines developed by Pfizer / BioNTech and Moderna. Then we could bring an end to this nightmare in a few months.

This illusion can now be called a delusion. We are in a new phase.

Our South African brethren have pointed the way. They had the foresight to set up a genomic surveillance system in a systematic, regionalized way to see how the virus was mutating day by day. This is the way molecular epidemiology and pandemic control should be undertaken.

What they’ve learned has been disturbing. They detected incredibly sudden changes in the virus’s mutational pattern. These were not single nucleotide changes of little consequence. These were multiple sudden changes to the viral RNA code that caused significant structural alterations to several areas of the spike protein on SARS-CoV-2. This has set off alarms in the scientific community. The spike protein is the structure that makes the vaccines work.

The changes we’ve witnessed were in regions of SARS-CoV-2 that were stable over the past year. The mutations were particularly concerning because they affect the Receptor Binding Domain (RBD), which defines the part of the spike protein where the virus attaches to the ACE2 receptor in human cells.

The current vaccines elicit neutralizing antibodies to the Receptor Binding Domain. Some of these mutations look so unusual, that scientists began to wonder whether the antibodies induced by the original vaccines can still bind and neutralize as intended. Might this new Receptor Binding Domain structure resist all neutralizing antibodies, from either natural infection or from vaccine-induced immunity? We’ve had to ask and answer that question. There are also changes to the viral RNA that encodes for another area we call N-terminal domain (NTD) that we don’t really understand.

The South Africans reported these changes first to the United Kingdom (UK), because the predominant strains circulating in South Africa in the early parts of the epidemic were similar to the most common one in the UK. It’s no surprise the two countries have similar viral strains, as there is considerable international travel between the two countries.

Once informed of the new strain from South Africa, now known as B.1.351,  UK molecular biologists started to look harder at strains circulating in their own country. They found a new variant that was starting to sweep over the country, called B.1.1.7. That new variant has driven a second wave of infection.

The second wave is worse than the first, as seen by increased rates of transmission and increased rates of hospitalization in the UK. This variant had one of the mutations in the RBD part of the genome, the one that appears associated with increased replication in the nose and transmission to other people, but fortunately not the changes that alter the neutralizing antibodies.

Very quickly, scientists put two and two together. The virus was evolving more rapidly than previously detected. Changes were occurring across two behavioral characteristics. And, the changes to these two characteristics were being detected in the same virus.

We have seen variations pop up over the past year. In June, we had a variation in the US where the original strain from Wuhan was overtaken by what we call the D to G614 strain; that’s what is mainly circulating here now. This strain also increased attachment to the ACE2 receptor, but the newer F105Y mutation enhances these characteristics even more and facilitates an even greater rate of spread.

This B.1.1.7 variant, commonly referred to as the UK variant, has now spread throughout Europe, and is being increasingly recognized in the US. The CDC predicts that this strain, with its evolved advantages, will become the predominant form of the virus circulating in the US over the next few months.

The B.1.351 variant, widely known as the South African variant, also has the increased transmissibility stemming from the mutation in the F105Y gene. But that’s not all. The South African variant has a couple more nasty mutations, one called E484K, that is associated with escape from an important neutralizing epitope that most people have after contracting COVID-19. That neutralizing epitope  is also found on antibodies induced by vaccination. This escape mutation on the part of the virus has been seen in other unrelated strains, so it seems to be a frequent way the virus tries to use to escape from people who have acquired immunity. So, people who have been infected with prior strains and developed immunity to those prior strains appear to be at an increased risk of re-infection with the B.1.351 variant.

We call this escape from neutralization or adaptive immune escape from the virus’s point of view.

This is what RNA viruses do. Influenza does this; HIV does it too.

In retrospect, we were a bit naïve about SARS-CoV-2, thinking that because this subgroup of coronaviruses edits its mutations more efficiently, we might escape from having lots of different strains. But natural selection is very powerful, as Darwin taught us. We have had more than 100 million confirmed cases of COVID-19 worldwide thus far, and the real number is certainly much, much bigger. When a virus spreads to this many hosts, this fast, it creates a lot of opportunity for the virus to adapt against the natural selection pressure placed on it by the human immune system.

The bad news is that we continue to give the virus opportunity to adapt. We’re tired of social distancing. Not everyone wears masks. We have limited supplies of vaccine at the moment. So, we find ourselves in a situation where mathematically, this pandemic is not going to stop anytime soon.

What do we do about it? This week brought us data that says we don’t have to panic. We do really have evidence that our current tools are going to be OK. Moderna reported that its vaccine, in lab tests, continued to produce robust neutralizing antibodies against the B.1.1.7 variant. The Moderna vaccine produced 6-fold lower titers of antibodies against B.1.351, but those antibody levels that are still higher than what are typically seen in cases of natural infection. Importantly, the nature of the mRNA technology makes it possible for Moderna to make a new mRNA construct very quickly to educate the immune system against this new B.1.351 variant, and that new “updated” vaccine can be tested in a small, fast clinical trial to validate its use as a “booster.”

Scientifically, this is the good news. But it’s only a piece of the puzzle. We have to create strategies to get us back up to the optimal state. This means vaccinating everyone globally as fast as possible. What impacts one of us impacts all of us, including here in the US. Ongoing community spread anywhere with this virus means it can spread everywhere in our interconnected world.

Besides findings from lab tests, we now have hard clinical evidence that our current vaccines will work as well against the UK variant as they have for the variants circulating in the US. The best evidence of this is a 14,500-person clinical trial of the Novavax vaccine which showed a 90% efficacy rate in a UK study where the UK variant constituted 30% to 40% of the strains circulating at the time of the trial. The antibody concentration from this two-dose vaccine is pretty similar to what we saw in the Moderna and Pfizer vaccines. Several scientific teams have now shown that sera from people vaccinated with either of these vaccines also neutralize the B.1.1.7 isolate as well as the isolate from Wuhan. That’s good news.

More importantly, we got data from the Johnson & Johnson (J&J) vaccine trial out of South Africa on Friday. We were lucky. We didn’t know when we conducted the J&J trial that there would be marked viral strain differences between South Africa and the US. In fact, when I worked with the company to design the trial, the reason we went to South America and South Africa for an international trial was because J&J is a global company and they wanted a globally developed vaccine. Their vaccine is also tailor-made for global vaccination efforts, since it can be given in a single shot, and shipped to remote parts of the world with standard refrigeration – no need for deep freeze.

My network was already working with J&J on their experimental HIV vaccines and we had great investigators in both South Africa and South America who were tackling the COVID-19 epidemic and wanted to help. We were conducting so many vaccine trials in the US, we felt we could distribute some of the work internationally and everyone would benefit. At the time these decisions were made last summer, we didn’t realize how fortuitous this decision would be. A month ago, after the South Africans noted that the B.1.351 variant was the main circulating strain in the country, we got nervous about whether the vaccine would be effective against this tough new variant.

Fortunately, this anxiety was alleviated when the data arrived from the 43,000-volunteer global trial. The J&J vaccine protected against hospitalization and death in 88% of the enrollees in South Africa! There were zero deaths in the vaccine group; six in the placebo group in South Africa. Overall, the vaccine was 57% effective against moderate and severe disease in South Africa.

The efficacy number in the US was 72%; in Brazil, 71%. Worldwide, the numbers worked out to 66 percent protection against moderate and severe disease.

Yes, we do have an 18% to 20% difference in the effectiveness in the J&J vaccine by region, and this is some source of concern. And I will add that the Novavax vaccine, which was shown to be 90% effective in the UK, showed 55% protection in South Africa. So, here too we saw a reduction in efficacy.

But to put it in perspective: What’s more important, do we develop these vaccines to reduce the frequency and severity of sore throats and cough? Or do we develop vaccines to prevent us from getting hospitalized, being put on supplemental oxygen, put on a ventilator, or dying?

I think all of us would take a vaccine that prevents us from dying, even though it might still mean a case of COVID-19 with a sore throat and a headache and body aches for a couple days. I’d take that deal.

In my next blog, I’ll talk more about the J&J vaccine and where it fits in the vaccine response in the US and globally. We need a bit more data to become public before we tackle this task. There are lots of opinions here and there’s nothing wrong with that. But it’s been a very good week. We now have two new safe and effective vaccines—Novavax and J&J. That can be nothing but great news.

As in all science, all good clinical trial outcomes lead to more good questions that we’ll need to answer to bring an end to this pandemic.

Dr. Larry Corey is an internationally renowned expert in virology, immunology, and vaccine development and a leader of the COVID-19 Prevention Network (CoVPN), which was formed by the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health to respond to the global pandemic. He is a Professor in the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center, past President and Director of Fred Hutch, and a Professor of Medicine and Virology at University of Washington.

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