SARS-C0V-2 vaccine & what we know about immunity

Someone is going to be very famous in 18 months or so. The postmodern Salk. People Magazine covers. Oprah Shows. Possibly even a shoe deal.

w
v

What scientists are learning about how long Covid-19 immunity lasts
Covid-19 antibody testing, long-term immunity, vaccines, herd immunity (and more!), explained.

https://www.vox.com/2020/7/22/21324729/getting-covid-19-twice-immunity-antibodies-vaccine-herd-immunity

Covid-19 continues to confound us all, with a growing list of symptoms, unexpected modes of transmission, and a wide range of outcomes, from benign to severe.

More than 600,000 people around the world have been killed by the virus, as of July 22. And for many survivors, Covid-19 is becoming a long-term condition too, with symptoms lasting for months.

Yet the majority of people infected with the virus recover on their own. And without a vaccine or much in the way of treatment options, the human immune system — a vast network of cells and tissues — remains the most potent defense against infection.

Scientists’ rapidly evolving understanding of this human immune response to Covid-19 is critical for answering some of the most important questions at this stage in the pandemic, including:

Can you catch Covid-19 twice?
What is the threshold for herd immunity — after which the pandemic might burn out?
Why are some people getting sicker than others?
How might a vaccine work, and how effective will it be?

Back in April, when the virus was only known to have been infecting humans for a few months, we wrote about Covid-19 and immunity, and we were told, over and over, it was too early to know what it would look like in the long term. Long-term impacts of a virus can’t be known when a virus is so new. We had to wait.

Since then, scientists have learned a lot about how the immune system responds to Covid-19, from the specific cells the body generates to fight the virus, to what this all means for a vaccine. The results aren’t all encouraging, but they are illuminating.
Here are some of the recent major findings about how human bodies respond to Covid-19, the implications for treating the disease and developing a vaccine against future infections, and how the pandemic could end.

Antibodies to SARS-CoV-2 wane over time. This is normal.

A recent study out of the United Kingdom sparked some scary headlines: “Covid-19 immunity from antibodies may last only months, UK study suggests,” as CNN put it.

Before this study, scientists knew that most people infected with SARS-CoV-2 — the virus that causes Covid-19 — generate antibodies. (Antibodies are the immune system proteins that seek out, stick to, and potentially deactivate viruses floating throughout the body. They can stop an infection in its tracks.)

Critically, they knew “the vast majority of individuals also develop neutralizing antibodies, which are that important subclass of antibodies that are able to basically independently kill the virus,” says Elitza Theel, the director of the infectious diseases serology laboratory at the Mayo Clinic, who was not involved with the research.

The study — which has not yet been peer-reviewed — asked: What happens to those neutralizing antibodies over time? The researchers followed 65 Covid-19 patients for up to 94 days after their symptoms started, analyzing their blood for antibodies, and found that in these patients, the antibodies declined over the three months.

“What we’re seeing with SARS-CoV-2 is that antibodies will peak at about 20 to 30 days after symptom onset, and then they decline,” Theel says of this and other recent evidence. “They seem to decline much more rapidly in individuals that were asymptomatic or had mild forms of the disease.”

It’s easy to read the results of this study, and wonder: Do people become vulnerable to reinfection over time?

If the answer is “yes,” that’s concerning. It means more reinfections. It could also result in delays in building herd immunity — the threshold at which new infections decline because fewer people are transmitting the virus or being infected. A less-than-robust human immune response after one exposure to the virus could also have implications for the effectiveness of an eventual vaccine. (More on that later.)

Also scary: There have been some anecdotal reports of people getting reinfected with the virus after recovering from a first infection and getting sick again after being exposed to the virus a second time. (But it’s still hard to tell how common reinfections will be. Ideally, doctors could collect viral genetic and antibody data from both bouts of infection and ask, “Is this the same virus flaring up again in my patient or a different one?” and, “Did my patient develop antibodies to the first infection, and did they wane before the second infection?”)

A pattern of declining antibodies after infection is typical, scientists say, and is seen in coronaviruses that cause the common cold. “This mostly looks normal,” Shane Crotty, an immunologist at the La Jolla Institute for Immunology, says.

The takeaway: We need not interpret the UK paper as evidence herd immunity is out of our reach or that everyone who has already had Covid-19 is necessarily at risk of reinfection three months later.

According to immunologists Nina Le Bert and Antonio Bertoletti at the Duke-NUS Medical School in Singapore, the media hype of fading antibodies is “a little pointless. … It is perfectly normal that antibodies are decreasing,” they tell Vox in an email.

And antibodies are, reassuringly, not the only part of the immune system that protects us from reinfection.

The immune system is more than just antibodies. A lot more.

That immunity doesn’t depend solely on antibodies is quite lucky for us. In fact, there are several parts of the immune system that may contribute to lasting protection against SARS-CoV-2.

One is killer T-cells. “Their names give you a good hint what they do,” says Alessandro Sette, who collaborates with Crotty at the La Jolla institute for Immunology. “They see and destroy and kill infected cells.”

Antibodies, he explains, can clear virus from bodily fluids. “But if the virus gets inside the cell, then it becomes invisible to the antibody,” he says.

That’s where killer T-cells come in: They find and destroy these hidden viruses.

While antibodies can prevent an infection, killer T-cells deal with an infection that’s already underway. So they play a huge role in long-term immunity, stopping infections before they have time to get a person very sick.

And it’s not just killer T-cells and antibodies. There are also helper T-cells, which facilitate a robust antibody cell response. “They are required for the antibody response to mature,” Sette says.

But wait, there’s more! There’s another group of cells called memory B-cells. B-cells are the immune system cells that create antibodies. Certain types of B-cells become memory B-cells. These save the instructions for producing a particular antibody, but they aren’t active. Instead, they hide out — in your spleen, in your lymph nodes, perhaps at the original site of your infection — waiting for a signal to start producing antibodies again.

When you are exposed to a new virus, it can take up to two weeks for your immune system to make the right antibody to destroy the infection. With the memory B-cells in reserve, instead of waiting two weeks or more to get antibody production going, it may only take a few days.

“Immunity” can mean many different things

From this bewildering array of factors, the bottom line is that “immunity” doesn’t mean just one thing: There are many types of immunity.

Immunity could mean a strong antibody response, which prevents the virus from establishing itself in cells. But it could also mean a good killer T-cell response, which could potentially stop an infection very quickly: before you feel sick and before you start spreading the virus to others.

“In many infections, the virus does reproduce a little bit, but then the immune response stops this infection in its tracks,” Sette explains. Also possible: “You do get infected, you do get sick, but your immune system does enough of a job curbing the infection, so you don’t get as sick,” Sette says.

Or immunity results from an awakening of memory B-cells. If an individual has memory B-cells and they’re exposed to the virus again, “that infection will stimulate a much faster antibody response to the virus, which would, theoretically lead to faster clearance of the virus and potentially less severe infection,” Theel says.

So reinfection may still be possible, but it may not be catastrophic. When a virus invades a body, generally, the body remembers.

What’s 😎 about the adaptive immune system is that both T and B cells become memory cells. The second time you encounter the same virus, memory B cells will produce much quicker & higher levels + quality of antibodies. Memory T cells provide quick and robust protection. (9/n) pic.twitter.com/L3ueBaJglH

— Prof. Akiko Iwasaki (@VirusesImmunity) July 22, 2020

Scientists still don’t know a lot about T-cells and Covid-19, but what they’ve learned is encouraging
Scientists don’t yet have data on long-term T-cells and memory B-cell response when it comes to SARS-CoV-2, but what they’ve seen so far is encouraging.

Crotty, Sette, and colleagues in June published a paper in the journal Cell looking at T-cell response in Covid-19 cases that did not require hospitalization.

“What we showed is that in average cases of Covid-19, where people got sick but didn’t have to go to the hospital, basically all of them made a CD4 T-cell [i.e., a helper T-cell] response,” Crotty says. “And most of them made a CD8 T-cell [i.e., a Killer T-cell] response. And so that looks pretty good.”

What’s left to figure out is how long these cells persist, too.

“We don’t know what happens in terms of memory,” Crotty says. Scientists still need more time to test the blood of those who have recovered. “Durability of immunity is a big question and really the only way to answer it is to wait. And so that’s a really hard thing.”

As for the persistence of memory B-cells? That also isn’t known (though studies show people are making them). But we do know B-cells generally seem to retain their memory for a long time. One report found that survivors of the 1918 flu pandemic had memory B-cells 80 years later.

Antibodies may wane, that does not necessarily mean immunity is lost. We do not yet know correlate protection. A study that has always fascinated me-memory BCells from survivors 1918 Flu pandemic isolated >90 years later. Human immune system is remarkable https://t.co/BbVS0fXi47

— Jeremy Farrar (@JeremyFarrar) July 15, 2020

All said, there’s reason for optimism that humans, at large, will achieve some form of lasting immunity to Covid-19 after an infection. “T cells response against coronaviruses appears long-lasting,” Le Bert and Bertoletti write. In their studies, they’ve found that people who recovered from the original SARS 17 years ago still have T-cells that can respond to the virus. That’s encouraging.

In their view, falling levels of antibodies aren’t so concerning. “What is important is that a level of B and T cell memory remain to be present,” they write.

They’ve also found that T-cells created to fight other coronaviruses may be useful in fighting Covid-19. So “a level of pre-existing immunity against SARS CoV-2 appears to exist in the general population,” they write. “What remained unresolved is whether pre-existing T cells are sufficient for protection.” (There’s some speculation that, in East Asia, Covid-19 may be less deadly because the population has greater previous exposure to other types of coronaviruses, which could grant them more preexisting immunity.)

Scientists have so far avoided risky human challenge trials of vaccines. They can’t intentionally reinfect people to see if they are protected, but they can do that with monkeys. And the results here are reassuring: Rhesus macaques did not get sick a second time after an initial bout of Covid-19.

The big question about long-term immunity

The big question lurking behind all this science is: What is the right mix — both in number and type — of antibodies, T-cells, and B-cells that lead to lasting, robust immunity to SARS-CoV-2? For instance, it could be that you don’t need a very high concentration of antibodies in your blood to successfully fight off the virus. It could be that T-cells play a bigger role in protection.

The answer to this big question is what scientists call the “correlate of immunity,” and for SARS-CoV-2, it’s not yet known.

“One thing that’s really I think important to kind of clarify is: Is there a minimum level of antibodies that are correlated to protective immunity?” Theel says.

But, also, true immunity to Covid-19 is unlikely to just require or need antibodies.

“There are people who, for example cannot make antibodies, and there are at least a couple of people in Italy who had Covid-19 and they survived and recovered [without having antibodies],” Crotty says. These patients got sick with pneumonia. “Nothing was measured about their immune response, but the implication there was that their T-cells presumably protected them in absence of antibody.”

Again, it’s unfortunately too soon to know the whole picture on Covid-19 immunity six months into the pandemic.

“We don’t really know exactly which pieces are required for protection; we don’t know how long they stay around,” Crotty says. “But, yeah, we’re trying our best to gather those data.”

Researchers are also making gains trying to understand how a dysfunctional immune response can lead one person to severe symptoms and need a ventilator, and another person to recover more easily. Recently scientists observed three different immune profiles that partially explain what makes the difference.

“There was no perfect correlation between immunotype and severe disease,” Nuala Meyer, a physician and researcher at the University of Pennsylvania says of the study. But some clues emerged. Those who had some of the worst outcomes, and spent some of the most time on a hospital ventilator, were more likely to have dysregulated T-cell response, she says. This may lead to (or just be correlated with) increased lung problems and poorer outcomes.

“The fear is that either too persistent an [immune] activation or too robust an activation might contribute to the organ damage that we see,” she says. The hope is, with a better understanding of the immune response to the SARS-CoV-2 virus, doctors could possibly prevent this overreaction from happening.

Does an antibody test tell you if you’re immune?

If you’ve read this far, congrats! That was a lot.

A more practical question people will have on their minds is what this all means on an individual basis. If you get a Covid-19 antibody test back and it’s positive, are you immune?

Sadly, these tests cannot confirm how protected a person is against Covid-19 and for what duration. “What’s important to understand is that all of the tests that are out there on the market right now, they detect antibodies, but they do not differentiate between binding antibodies or neutralizing antibodies,” the Mayo Clinic’s Theel says.

So all you really can conclude from an antibody test is that you’ve been exposed to the virus. (Plus, these tests are not perfectly accurate to begin with and their accuracy can change depending on the prevalence of the virus.) It can’t tell you about reinfection risks or immunity.

“That’s the wish, right, that you get a positive antibody result and you think ‘I’m immune,’ but I think we cannot say that. So in my opinion, antibody testing at the individual patient level is really limited in utility,” Theel says.

As a result of antibody testing, “you shouldn’t change any of your masking or other personal protective equipment or strategies,” she says. If you want to do something proactive with your positive test result, you can see if you can donate blood plasma. The antibodies in your plasma could potentially help a Covid-19 patient recover.

What our evolving understanding of immunity means for a Covid-19 vaccine
Take all that complicated nuance about the immune system, think about deliberately tweaking all those parts to do exactly what we want them to do, and you’ll get a sense of the challenge that vaccine researchers face.

A vaccine is a drug that teaches the immune system to counter a threat like a virus without causing illness. It can reduce the likelihood of a severe disease or prevent an infection altogether. That makes vaccines powerful, life-saving tools. But developing them is a costly, slow, and tedious process. Many attempts at making vaccines will fail.

While there is no guarantee that a successful Covid-19 vaccine will be made, some scientists are optimistic that one or more will be available in record time.

One big reason: Most people survive the infection on their own, showing that the immune system can be coached to fend off the pathogen. The task now is to figure out just what kind of target the immune system needs to practice on to ensure it’s ready to handle the real threat when it arrives.

At the moment, there is an unprecedented global effort to create a Covid-19 vaccine at an astonishing speed. More than 150 candidates are under development and many already in human trials just months after the virus was discovered. Research groups have already posted some promising results and are beginning large-scale testing. Manufacturers are building out factories to make billions of doses and governments are investing billions of dollars.

Just this week, research teams in China and the UK published a pair of papers in the journal The Lancet showing their results from early trials of Covid-19 vaccines. They both used a version of the adenovirus — a different virus from SARS-CoV-2 — modified to ensure that it doesn’t cause disease. Instead, the adenovirus vector presented a piece of SARS-CoV-2 as a way to induce an immune response.

Both research teams found that their Covid-19 vaccines using the adenovirus were safe, with minimal complications in test subjects. The vaccines also generated immune responses with antibodies and T-cells in the study group.

“As far as the results that have been published [this week], they are really exciting, and I’m cautiously optimistic about what they mean for the development of an effective coronavirus vaccine,” says Naor Bar-Zeev, an associate professor of international health and a vaccine researcher at the Johns Hopkins Bloomberg School of Public Health, who published a commentary article about the findings.

But nothing about this pandemic is simple, and the push to develop a vaccine is no exception. “Lots of unanswered questions remain and obviously we need to go through the difficult process of large-scale phase 3 trials,” Bar-Zeev says.

For one thing, the wide spectrum of immune responses to the SARS-CoV-2 virus means that there will likely be a range of responses to a vaccine. Not everyone will receive the same level of protection from a given vaccine and some may not get any protection at all. What’s more, the immune response in older people is different from that in children, for example, so it’s hard to make a one-size-fits-all vaccine.

“Some people simply won’t have the genetic equipment to recognize a particular pathogen well. That’s part of why people react differently to diseases,” said Benjamin Neuman, a virologist at Texas A&M University Texarkana, in an email. “For this reason, we will ideally need to have different vaccines available for different people.”

Right now, most of the vaccines being investigated are aiming at just one protein from the virus, most commonly the spike protein of the SARS-CoV-2. This protein is what the virus uses to get inside human cells, making it an important target. Getting lasting protection from Covid-19 may require multiple doses of these types of vaccines, or vaccines targeted to different parts of the virus. The results of inoculation can vary, from sterilizing immunity, which completely prevents an infection, to protection only against severe outcomes from the virus but not mild ones.

The question of whether a vaccine will lead to effective immunity can only be answered with large randomized controlled clinical trials. Thousands of people will have to receive doses of the vaccine and be compared to thousands of people who didn’t to see how well it keeps the virus at bay. It’s time-consuming and expensive, but it’s essential for bringing a vaccine to fruition.

Overall, from what Crotty has seen from his studies on the immune response to the virus, he feels “optimistic about a vaccine.” The immune profile suggests that vaccine development strategies have worked in the past. “Our data show people can recognize this virus and make reasonable [immune] responses to it,” Crotty says. “And that’s the type of thing you’d need to be trying to mimic with a vaccine. So that was encouraging.”

What will it take to get to herd immunity?

To end the pandemic, it’s clear simply having a vaccine isn’t going to be enough. An effective vaccine would certainly be a vital tool, but how it’s deployed and what people do in the meantime will shape how the crisis fades away.

In the end, we will still need some form of herd immunity to durably curtail transmission, where a large enough share of a population is immune to the virus such that new infections decline significantly because the virus can’t be continually passed on. That kind of protection is critical for people who cannot be vaccinated but are vulnerable to the illness, like the immunocompromised. Once achieved, there may be small outbreaks, but the raging pandemic will subside and eventually, life can return to something approaching normal.

Depending on how readily a disease can spread, the threshold for herd immunity can be anywhere from 60 percent to 90 percent of a population. Some models of Covid-19 have found that herd immunity could be achieved at 20 percent.

And it’s not a firm endpoint; an epidemic can recede on its own before herd immunity is reached, or an uncontrolled pandemic can rage well past this benchmark.

One way to reach this point is to allow a virus to run rampant within a population until sufficient numbers of people have been infected, but this is a costly and deadly path. That has been clear in Sweden, which took a less extreme version of this approach.

Letting a virus loose also increases the chances that it will overshoot the herd immunity threshold and continue spreading even if 70, 80, or 90 percent of the population is immune. Most parts of the world are still in single-digit percentages when it comes to the number of Covid-19 cases, so herd immunity by uncontrolled exposure is still a long way off.

The alternative scenario requires mass vaccination. But even with this route, it’s not as simple as whether we have a vaccine or not.

“It’s important to realize that a vaccine is not a binary thing,” says Bruce Y. Lee, a professor of health policy and management at the CUNY School of Public Health. “It can vary in terms of its characteristics for how effective it can be.”

Using computer models, Lee found that there’s a sliding scale between how effective a vaccine is and how many people have to get it to achieve herd immunity. Effectiveness in this case means the share of vaccinated people who are immune to the virus out of all who received the vaccine. He co-authored a paper in the American Journal of Preventive Medicine with his findings last week.

The results showed that if you can achieve a vaccination rate of 100 percent across a population, a vaccine needs to be at least 60 percent effective. If coverage falls to 75 percent, then a vaccine needs to have at least 70 percent efficacy.

“People should not look at a vaccine like they would a treatment. It’s not just that I get it, but other people have to get it as well,” Lee says. “The more people that get vaccinated in general in the population, the less the virus gets an opportunity to spread.”

However, these results are predicated on a mass vaccination strategy alone. Other measures — social distancing, wearing masks, rigorous hygiene, testing, tracing, and isolation — can also play an important role in stopping the virus within a population. While they won’t change the threshold of herd immunity, these tactics can limit the number of people who are infected with Covid-19 at a given moment, according to Lee. By reducing the number of people infected, it’s easier to ensure that the susceptible people around them are protected by a vaccine. This highlights the need to maintain many of the pandemic control measures deployed right now even after a vaccine starts to become widely available.

Herd immunity might also be achievable in the case there is no vaccine, and even if reinfections occur.

“My expectation is that reinfections will actually be normal — but it doesn’t mean herd immunity is not achievable,” Michael Mina, an epidemiologist at Harvard, tells Vox in an email. He expects second infections will typically be mild, and “will not transmit much and will serve as immunological boosting events more than they do as transmission events that chip away in any substantial fashion against herd immunity.” Which is to say: Reinfections may serve to increase immunity in individuals.

Another variable to consider is how long immunity from a vaccine would last. Even if it isn’t permanent, if immunity lasts longer than the acute phase of the pandemic — say, around two years — that’s still useful and could drive infections down. But if a vaccine provides immunity that lasts only a few months, shorter than the duration of a vaccination campaign, that would likely mean people would need regular re-vaccinations or booster shots. Otherwise, even the immunized would face risks of reinfection.

And the current state of the pandemic adds yet another confounding factor for vaccination, particularly in the United States, with so many people infected and with the number of new cases continuing to rise.

“The problem is that since there are already so many people that are not protected and that have the infection, you have to surround yourself with so many people who are protected before you can have this concept of herd immunity,” says Maria Elena Bottazzi, a co-director of the Texas Children’s Hospital Center for Vaccine Development who also co-authored the vaccine modeling study with Lee.

With numerous clusters of infection like we have now in the United States, far more people need to be vaccinated to contain them, and the vaccine would need to have a higher level of efficacy. It would behoove everyone to try to contain the virus and limit the number of new infections to less than one per 1 million people per day, according to Bottazzi. “If we flatten the curve, we can then probably still try to get the most efficacious vaccine, but then arguably we don’t have to worry about reaching these 80, 90 percent [vaccine efficacies] that we really need,” she says.

So the prospect of a vaccine, even at a record pace, should not be a reason to relax the effort to contain the virus. It will take years to deliver the vaccine to billions of people around the world, and the virus may continue causing mayhem in the meantime. While we can’t control the immune response inside our bodies, we can set the stage for herd immunity by reducing the spread of Covid-19 now.

Our first line of defense against the virus is the cells within us, but stopping the outbreaks will depend on the whole world working together.