Differences in Antibody Responses Linked to COVID-19 Outcomes

In late February, as COVID-19 tore through nursing homes in Seattle, some patients were seen by University of Washington physician and immunologist Helen Chu at Harborview Medical Center. Chu puzzled why certain COVID-19 patients, who seemed fine at first, would rapidly deteriorate from one day to the next and die, recalls her collaborator Galit Alter of the Ragon Institute of Massachusetts General Hospital, MIT, and Harvard.

The survivors really picked different functions than the deceased. They just leveraged their antibodies in a different way.

—Galit Alter, Ragon Institute

In search of answers, Chu and her colleagues collected blood samples from 22 patients upon hospital admission and sent them to Alter, whose group specializes in a branch of immunology called “systems serology.” This combines experimental techniques to analyze the features and functions of antibodies with computational approaches to discern, for instance, which ones correlate with immunity. From previous studies of viral infections including HIV, tuberculosis, and malaria, Alter has learned that it’s not the quantity of antibodies that’s predictive of immunity, but rather, their different functions and qualities, and, importantly, how they act collectively as a “swarm,” she explains.

Alter and her colleagues profiled the antibodies of the 22 patients; 12 had recovered from COVID-19 and 10 had died. The scientists focused on SARS-CoV-2-specific antibodies that target the virus’s key proteins, including the spike protein, which it uses to enter human cells, and the nucleocapsid protein, which encloses its genetic material. For each viral target, the researchers documented a range of antibody characteristics, such as the quantity of specific antibody types and their ability to stimulate other immune cells such as microbe-devouring neutrophils.

The team detected no difference in the overall amount of antibodies between survivors and those who died, nor in the antibodies’ overall capacity to neutralize the virus in vitro. However, when the team used computational methods to analyze the functional differences between the two groups, they found a combination of five antibody features distinguished them from one another. Overall, survivors had a much stronger antibody response to the spike protein, whereas antibody responses in those who died were more focused on the nucleocapsid protein.

It’s not that survivors have more spike-targeting antibodies, Alter notes, rather, their antibodies are “targeting [the spike] more than they’re targeting [the nucleocapsid].” In fact, in the Seattle cohort, these five features proved even more predictive of a patient’s recovery or death than factors such as age or sex.

The team also validated this approach in a larger cohort of COVID-19 patients from a Boston hospital, 20 of whom had recovered and 20 of whom had died. There too, survivors’ antibodies were “laser-focused” on targeting the spike protein, whereas antibodies tended to focus on the nucleocapsid protein among those who died, Alter says. “The survivors really picked different functions than the deceased. They just leveraged their antibodies in a different way.”

An outstanding question is whether the nature of a patient’s antibody response is actually what determines whether they recover or die, or if it’s simply a symptom of the overall function of the immune response, Alter says.

That said, the data do provide plausible hypotheses on how antibodies could contribute to the body’s defeat of SARS-CoV-2, she adds. Spike-focused antibodies might be better at helping the body clear the virus, which could help other components of the immune system drive down inflammation associated with COVID-19. The antibodies’ focus on the nucleocapsid in other patients could have to do with the fact that some people have greater viral loads in the lung, causing the immune system to encounter large quantities of the nucleocapsid protein—which is generally much more abundant than the spike protein. This could cause antibodies to become “distracted” from the right target—the spike protein—and tailor their response towards the nucleocapsid protein.

While preliminary, the findings could offer a path forward in developing a prognostic tool for clinicians to discern relatively early on in the course of disease which patients are likely to fare worse and therefore need more careful attention or should be prioritized for certain types of therapies, Alter suggests. Other investigators are looking into cytokines as disease severity markers, but the trouble is that those aren’t specific to SARS-CoV-2 infections.

See “Neutrophil Extracellular Traps Could Auger Severe COVID-19”

The findings could be useful for vaccine scientists, notes Danny Altmann, an immunologist at Imperial College London who wasn’t involved in the research. “You need some detailed info on the correlates of protection—otherwise how can you ever know if your vaccine elicits them,” he writes to The Scientist in an email. “Up to now a lot of [COVID-19] findings have been a little general. With studies like this, we get into some real granularity of what a protective response looks like.” Notably, most vaccinologists are focusing on the spike protein, which is probably a good thing, Alter adds.

The authors acknowledge several limitations of the research, including the small size of the Seattle cohort. However, Alter’s group was able to validate the correlations they uncovered in a larger cohort of 170 patients, whose antibody responses were tracked over time, in a soon-to-be published study.

Collectively, the findings are adding to a growing body of research on the interaction between SARS-CoV-2 and the human immune response, Pulendran says. Just last week in Science, he and his colleagues investigated the source of higher levels of inflammatory cytokines in severely affected COVID-19 patients. Surprisingly, the blood-borne monocytes and dendritic cells that usually secrete these cytokines were too “functionally sluggish” to respond to viral protein, Pulendran says. Rather, the cytokines appeared to be emanating from the lung, he explains.

How this dysfunctional innate immune response relates to emerging peculiarities of the adaptive immune response—such as T cell and antibody immunity—is still a mystery. “The field of COVID immunology is at a stage where there are many exciting observations and insights about one aspect of the immune system or another aspect,” Pulendran says. “The challenge over the coming weeks and months will be [to figure out] how to fit these all together.”

C. Atyeo et al., “Distinct early serological signatures track with SARS-CoV-2 survival,” Immunity, doi:10.1016/j.immuni.2020.07.020, 2020.