NIH study finds naturally acquired immunity is weak against SARS-CoV-2 variants

Immunity acquired after recovering from a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not sufficient in protecting against reinfection from variants, finds a new study published on the bioRxiv* preprint server.

Study: Serum from COVID-19 patients early in the pandemic shows limited evidence of cross-neutralization against variants of concern. Image Credit: Alexey Boldin /

Led by Andrea Marzi of the National Institute of Health, the findings of the current study indicate that people who were infected in early 2020 had limited neutralizing antibodies against the Alpha, Beta, and Delta SARS-CoV-2 variants. The number of neutralizing antibodies gained after infection depends on the severity of the infection.

“The more fully we understand effective immune responses to this pathogen, the greater our ability to successfully treat those who are infected, and vaccinate those we hope to protect against infection.”

About the study

The researchers studied the immune response in 131 serum and plasma samples that were donated by 55 patients who had confirmed COVID-19 early in the pandemic. Samples from 20 uninfected patients were used to compare cytokine, chemokine, and antibody responses.

The average age of the patients was 58 years, of which 45% of patients were female and 49% donated multiple samples. Patients who gave only one sample were on average 44 years old, 75% of whom were female.

Samples were grouped based on the patients' disease severity. Mild to moderate indicated minor symptoms and mild pneumonia. Severe symptoms included patients who experienced low oxygen levels, trouble breathing, or 50% lung involvement on imaging. Critical disease severity meant a patient had undergone respiratory failure, shock, or multiorgan system dysfunction.

Cytokine and chemokine levels correlate with disease severity

Thirty-eight different types of cytokine and chemokines were measured in the serum and plasma samples.

SARS-CoV-2 infection altered the number of cytokines and chemokines in the body. Increasing cytokine and chemokine levels were associated with disease severity; however, this rise in cytokine and chemokine levels was also observed from the mildest to the most critical of illnesses.

Patients with a mild to moderate infection had elevated levels of human monocyte chemotactic protein-3 (MCP-3), interleukin 1α (IL-1α), tumor necrosis factor β (TNFβ), IL-4, IL-5, IL-6, IL-8, IL-9, and IL-13 compared to patients with critical infections and uninfected adults. Additionally, a higher level of IL-15 was observed in patients with mild infections as compared to the uninfected.

Patients who recovered from critical infections also showed higher soluble CD40L (sCD40L) and interferon gamma-induced protein 10 (IP-10) levels than uninfected adults.

Because some patients donated multiple samples, the researchers investigated how the immune response against SARS-CoV-2 changed over time. Their findings confirmed no significant changes in cytokine or chemokine levels.

Increased IL-6 and IP-10 levels in patients who died from COVID-19

Patients with critical infections who did not survive had significantly more IL-6 and IP-10 levels as compared to uninfected adults. Moreover, patients who survived critical illness showed significantly increased sCD40L levels than the control group.

“Although serum and plasma from fatal disease patients contained more sCD40L than serum and plasma of normal controls, it was not significantly increased relative to serum and plasma from patients who recovered from infection, indicating that this soluble mediator may be important for surviving COVID-19.”

Antibody responses

Patients with mild to moderate infection had a significantly higher amount of immunoglobulin G (IgG) antibodies that were specific to the SARS-CoV-2 receptor-binding domain (RBD) than uninfected adults. However, only about half of the patients with mild to moderate COVID-19 had produced RBD-specific IgGs.

In critical infection, recovered patients showed two logs greater neutralizing antibody titers than the control group and one-and-a-half logs higher than patients with mild to moderate illness.

Importantly, the presence of RBD-specific IgG did not predict the patient’s disease outcome, as demonstrated by the fact that there was not a significant difference observed in the antibody titers between patients who had recovered from COVID-19 and those who did not.

Neutralizing antibodies were weak against VOC

The researchers tested the efficacy of neutralizing antibodies in naturally acquired immunity against the Alpha, Beta, and Delta variants. Subsequently, the serum and plasma samples with high neutralizing antibody titers were exposed to these three SARS-CoV-2 variants.

To this end, these antibodies were able to neutralize the variants; however, these were significantly low antibody titers as compared to those that were able to neutralize the original strain of SARS-CoV-2. Interestingly, the titers against the Alpha variant were significantly higher as compared to those that were used against the Beta and Delta variants, thus demonstrating that individuals with neutralizing antibody titers are still vulnerable to reinfection with the currently circulating Delta variant.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Jocelyn Solis-Moreira

Written by

Jocelyn Solis-Moreira

Jocelyn Solis-Moreira graduated with a Bachelor's in Integrative Neuroscience, where she then pursued graduate research looking at the long-term effects of adolescent binge drinking on the brain's neurochemistry in adulthood.


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