Antibody response following SARS-CoV-2 mRNA vaccine is greater than natural infection

Researchers in the United States have provided the first evidence that messenger RNA (mRNA)-based vaccines against severe acute respiratory coronavirus 2 (SARS-CoV-2) induce a broader array of antibody subtypes against the viral spike protein than natural infection does.

The novel SARS-CoV-2 virus is the agent responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic, and the spike protein is the main structure the virus uses to bind to and infect host cells. The spike protein is the primary target of neutralizing antibodies following natural infection or vaccination.

The team from Icahn School of Medicine at Mount Sinai in New York also showed that vaccine-induced immunoglobulins (antibodies) were more potent than those induced by natural infection in mediating activation of the complement cascade – a part of the immune system that boosts the ability of antibodies to target invading microbes.

Catarina Hioe and colleagues say the findings highlight the superiority of vaccination over natural infection in eliciting functional antibody responses against SARS-CoV-2.

A pre-print version of the research paper is available on the medRxiv* server, while the article undergoes peer review.

Study: SARS-CoV-2 mRNA vaccines induce a greater array of spike-specific antibody isotypes with more potent complement binding capacity than natural infection. Image Credit: Corona Borealis Studio / Shutterstock

More about vaccine-induced antibodies

In the United States, three vaccines have received authorization for emergency use to protect against SARS-CoV-2 infection. These include two mRNA-based vaccines from Pfizer-BioNTech and Moderna and one adenovirus-vector vaccine from Johnson & Johnson.

All three vaccines induce antibodies that target the membrane-anchored spike glycoprotein. This protein contains the receptor-binding domain (RBD) that attaches to the host cell receptor angiotensin-converting enzme2 (ACE2) as the initial stage of the infection process.

While the primary antiviral function of antibodies is to neutralize virions, these antibodies also mediate non-neutralizing effector functions via their fragment crystallizable (Fc) fragments, such as activation of the complement system.

In the case of SARS-CoV-2, when anti-spike immunoglobulins bind to virions, infected cells, or spike proteins, immune complexes form that are capable of engaging Fc receptors (FcRs) or complement via these Fc fragments.

“The FcR engagement triggers a cascade of intracellular signals critical for Fc-mediated activities, such as Ab-dependent cellular phagocytosis (ADCP) and Ab-dependent cellular cytotoxicity (ADCC),” explains Hioe and colleagues.

While the COVID-19 vaccines that are currently being used for mass immunization have been shown to elicit neutralizing antibody responses, the full properties of these antibodies are not yet known, say the researchers.

“In particular, Fc-mediated activities and the associated immunoglobulin isotypes elicited after vaccination have not been studied,” they write.

What did the researchers do?

Using a multiplex bead antibody binding assay, the team analyzed the spike- and RBD-specific immunoglobulin (Ig) antibody isotypes in plasma and saliva samples collected from seven mRNA vaccine recipients and from eight unvaccinated COVID-19 convalescent patients.

Two of the vaccinees had received the Pfizer-BioNTech vaccine, while five had received the Moderna vaccine, and samples were collected between 15 and 37 days following the second dose.

The vaccine-induced antibodies were examined for Fab-mediated virus neutralization and Fc-mediated activities, including ADCP and complement deposition.

What did the study find?

All vaccinated and convalescent participants had detectable saliva and plasma levels of spike-specific antibodies.

A strong correlation was observed between the plasma and saliva anti-spike Ig levels following either natural infection or vaccination.

The researchers say that a previous study also reported that similar levels of anti-spike Igs were detected in plasma and saliva following SARS-CoV-2 infection.

“These data indicate the potential use of saliva for monitoring of anti-spike antibody responses in vaccinated and convalescent individuals,” they write.

Vaccine-induced antibody response were dominated by the IgG1 isotype

The plasma and saliva antibody responses that were induced by vaccination were dominated by the IgG1 isotype.

“This study provides the first evidence that COVID-19 mRNA vaccines induced plasma and saliva antibody responses dominated by IgG1,” says Hioe and colleagues.

Interestingly, compared with natural infection, vaccination also induced antibody responses marked by higher levels of IgG2, IgG3, and IgG4 and greater ratios of (IgG1+IgG3)/(IgG2+IgG4).

Furthermore, while plasma neutralizing activity and ADCP potencies were similar between the vaccinated and convalescent individuals, vaccine-induced plasma antibodies were more potent in mediating complement binding and activation.

“We showed here that complement binding to spike-antibody immune complexes was stronger in plasma from vaccinated versus convalescent groups,” writes the team.

“The data highlight the superiority of vaccination”

The researchers say the study provides the first evidence that SARS-CoV-2 immunization induces a greater breadth of spike-specific Ig isotypes and more potent complement binding capacities than natural infection.

“The data highlight the superiority of vaccination in eliciting functional antibody responses against SARS-CoV-2,” concludes the team.

*Important Notice

medRxiv 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:
  • Hioe C, et al. SARS-CoV-2 mRNA vaccines induce a greater array of spike-specific antibody isotypes with more potent complement binding capacity than natural infection. medRxiv, 2021. doi:,

Posted in: Medical Research News | Disease/Infection News

Tags: ACE2, ADCC, Adenovirus, Angiotensin, Antibodies, Antibody, Assay, Cell, Coronavirus, Coronavirus Disease COVID-19, Cytotoxicity, Glycoprotein, Immune System, Immunization, Immunoglobulin, Intracellular, Medicine, Pandemic, Phagocytosis, Protein, Receptor, Research, Respiratory, RNA, SARS, SARS-CoV-2, Severe Acute Respiratory, Spike Protein, Vaccine, Virus

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Written by

Sally Robertson

Sally first developed an interest in medical communications when she took on the role of Journal Development Editor for BioMed Central (BMC), after having graduated with a degree in biomedical science from Greenwich University.

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