Eighteen months after the first officially reported SARS-CoV-2 cases appeared in Wuhan we can now begin to investigate questions that were impossible to answer early on in the pandemic, such as what kind of immunity is generated from a natural infection, how long could one be protected from re-infection, and does vaccination generate better immunity than natural exposure to the virus?
A recent preprint study, led by scientists from the University of Oxford, offers the most thorough account of immune responses in recovered COVID-19 patients to date. Nearly 80 healthcare worked were closely followed for six months post-infection and the researchers used a novel machine-learning approach to analyze immune biomarkers.
“We found that individuals showed very different immune responses from each other following COVID-19, with some people from both the symptomatic and asymptomatic groups showing no evidence of immune memory six months after infection or even sooner,” explains study author Christina Dold.
In general the research saw a correlation between disease severity and lasting immune response. Over 90 percent of asymptomatic cases showed no measurable immune response six months later. A quarter of symptomatic cases lacked lasting immunity six months after infection.
A little more worrying, however, was the finding that very few serum samples from infected subjects mounted antibody responses against newer variants of the virus. Dold says this seems to suggest those infected with the original SARS-CoV-2 strain in 2020 may have little protection from some of the newer variants beginning to circulate.
“Our concern is that these people may be at risk of contracting COVID-19 for a second time, especially with new variants circulating,” says Dold. “This means that it is very important that we all get the COVID vaccine.”
But why would immunity generated by a vaccine be any different from natural infection?
“The honest truth is, we don’t know,” says Sabra Klein, an expert in immunology from the Johns Hopkins Bloomberg School of Public Health. “The immune system of people who have been infected has been trained to target all these different parts of the virus called antigens. You’d think that would provide strongest immunity, but it doesn’t.”
Natural immunity is unpredictable
One of the biggest problems with natural immunity generated from a SARS-CoV-2 infection is just how variable and unpredictable it can be. A striking study published earlier this year found a stunning spectrum of natural immune responses in recovered COVID-19 patients. Although comfortingly, the paper saw immune responses from a natural infection lasting at least eight months, it also indicated some recovered patients displayed immunity levels 100 times higher than other patients.
"So if you were playing a basketball game and one person scored one point and the other person scored 100 points, you would not consider those equivalent performances," explains corresponding author Shane Crotty to USA Today. "And so that's the way we think about the immune responses as well. They're there, but not everybody's equal."
A more recent study, yet to be peer-reviewed and published, compared long-term antibody responses between naturally infected subjects and those immunized with a mRNA vaccine. It found after two vaccine doses antibody levels were up to 10 times higher than plasma from those following natural infection.
The RBD clue
A clue as to why vaccine-induced immunity could be stronger than natural infection comes in a robust new study published in the journal Science Translational Medicine. This research, from a team at the Fred Hutchinson Cancer Research Center, focused on a specific part of the SARS-CoV-2 virus called the receptor binding domain (RBD).
Everyone has probably heard of SARS-CoV-2’s infamous spike protein. It is this novel protein that allows the virus to infect humans by attaching to a receptor called ACE2, present in some of our cells.
Acting as a kind of interface between the viral spike protein and ACE2 receptors in human cells are RBD fragments. These are like anchors, helping the virus fuse with ACE2 receptors and ultimately infect human cells.
The new research analyzed thousands of possible RBD variants. The goal was to compare how well vaccine-elicited antibodies targeted RBDs compared to antibodies generated by natural infection.
“By closely examining the results, the researchers uncovered important differences between acquired immunity in people who’d been vaccinated and unvaccinated people who’d been previously infected with SARS-CoV-2,” writes Francis Collins, director of the National Institutes of Health, in a statement explaining why vaccination is important, even for those previously infected.
“Specifically, antibodies elicited by the mRNA vaccine were more focused to the RBD compared to antibodies elicited by an infection, which more often targeted other portions of the spike protein. Importantly, the vaccine-elicited antibodies targeted a broader range of places on the RBD than those elicited by natural infection.”
This new research finding offers insight into how vaccination could be more protective against newer SARS-CoV-2 variants. But, it still is unclear exactly why vaccination acts so specifically on RBD in this way.
Klein hypothesizes the reason behind strong vaccine immunity could be the way vaccines present the immune system solely with a large volume of spike proteins. This extreme focus on just one part of the virus could heighten our ability in developing effective antibodies.
“It’s like a big red button sitting on the surface of the virus. It’s really sticking out there, and it’s what our immune system sees most easily,” says Klein. “By focusing on this one big antigen, it’s like you’re making our immune system put blinders on and only be able to see that one piece of the virus.”
Another hypothesis raised by the research team behind the new RBD study is that vaccines, mRNA vaccines in particular, present antigens to the immune system in a way that is very different to natural infection. This includes the fact that vaccines expose different parts of the body to antigens, which does not occur through natural viral infection.
“… natural infection only exposes the body to the virus in the respiratory tract (unless the illness is very severe), while the vaccine is delivered to muscle, where the immune system may have an even better chance of seeing it and responding vigorously,” explains Collins.
Hybrid Immunity
A growing body of research is finding one dose of a vaccine in previously infected subjects can produce a larger immune response than two doses given to uninfected individuals. Most recently a study led by UCLA affirmed previously infected COVID-19 subjects only required one mRNA vaccine dose to produce a strong antibody response.
“Our data suggest that a person who previously had COVID-19 has a huge response after the first mRNA vaccination and has little or no benefit from the second dose,” says Otto Yang, senior author on the study. “It is worth considering changing public health policy to take this into account, both to maximize vaccine usage and avoid unnecessary side effects.”
Crotty, a vaccine scientist from La Jolla Institute for Immunology, explains how combining natural immunity and vaccine-generated immunity can synergize to produce a kind of “hybrid vigor immunity.” This means those previously infected with SARS-CoV-2 will be better protected against newer variants after a vaccine shot compared to just relying on protection from natural infection.
“… neutralizing antibodies against B.1.351[the beta variant] after vaccination of individuals previously infected with non-B.1.351 SARS-CoV-2 were - 100 times higher than infection alone and 25 times higher than after vaccination alone - even though neither the vaccine nor infection involved the B.1.351 spike,” Crotty writes in a recent perspective article.
With the rapid rise of the delta variant, which seems set to become the predominant SARS-CoV-2 variant, these new findings serve as a reminder of the importance of vaccinations, regardless of whether one has been previously infected.
All current vaccines have been found to offer good protection from new SARS-CoV-2 variants. And, as Francis Collins stresses, acquired immunity from vaccines offers our best hope at getting this pandemic under control.
“Our best hope of winning this contest with the virus is to get as many people immunized now as possible,” writes Collins. “That will save lives, and reduce the likelihood of even more variants appearing that might evade protection from the current vaccines.”
