Study: Macaque-human differences in SARS-CoV-2 Spike antibody response elicited by vaccination or infection. Image Credit: exs_yori/Shutterstock

SARS-CoV-2 antibody profiles in vaccinated and convalescent macaques compared to humans

Despite macaques being closely related to humans, new research from Macaque monkeys suggests severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody levels differ from humans in their ability to recognize certain epitopes— the area where the antibody binds to the antigen. Additionally, Macaque antibody levels showed a wide range of responses towards epitopes with SARS-CoV-2 mutations that promote immune escape.

Study: Macaque-human differences in SARS-CoV-2 Spike antibody response elicited by vaccination or infection. Image Credit: exs_yori/ShutterstockStudy: Macaque-human differences in SARS-CoV-2 Spike antibody response elicited by vaccination or infection. Image Credit: exs_yori/Shutterstock

Briefly, antibodies from vaccinated humans were the only ones to recognize peptides from epitopes on the N-terminal and the C-terminal domain. Humans with naturally acquired antibodies had weak recognition of the C-terminal domain. Of all the groups, macaques with naturally acquired antibodies had a stronger response to upstream and downstream regions of the fusion peptide epitope.

Given that animal studies are a common way to test out vaccines before testing in humans, the findings suggest that Macaque monkeys may not be the ideal model when testing for SARS-CoV-2.

This new study was recently published on the bioRxiv* preprint server.


The researchers used a phage-based deep mutational scanning approach to look at the types of epitopes targeted by antibodies acquired from vaccination or after SARS-CoV-2 infection. They also looked at antibody escape pathways in each epitope which would indicate the strength of antibody binding.

There were four groups involved in the study: vaccinated pigtail macaques, vaccinated humans, rhesus macaques who had a SARS-CoV-2 reinfection, and humans with naturally acquired immunity.

Vaccinated macaques received their version of an mRNA vaccine. Plasma samples for measuring antibody levels were collected 42 days after the first dose or 14 days after the second dose.

Similarly, people who were vaccinated had received two doses of the Moderna COVID-19 vaccine. Serum samples were donated 36 days after the first dose/a week after the second dose.

Infected macaques recovered twice from SARS-CoV-2 infection. The infections were induced 6 weeks apart and serum samples were collected 2 weeks after the second infection. Likewise, people who had received antibodies after recovering from mild infection were sick for a median of 67 days.

The study

The peptides of antibodies from each individual were enriched to study antibody recognition of the spike protein.

Most antibodies did not recognize the SARS-CoV-2 receptor binding domain because of the conformational changes observed in epitopes of that particular region. The researchers note it is harder to capture antibody responses because the Phage-DMS can only detect epitopes with linear sequences.

One exception was seen in vaccinated pigtail macaques. Some had strong antibody binding to a receptor-binding domain epitope. However, while it wasn’t consistent, four of the five vaccinated macaques also showed an antibody response to the same epitope. The findings suggest the antibody binding in the receptor-binding domain was not based on vaccination.

Vaccinated humans more than vaccinated macaques had antibodies with a preference for recognizing the SARS-CoV-2 N-terminal domain, C-terminal domain, and fusion peptide.

Macaques with naturally acquired immunity had more antibodies than humans with naturally acquired immunity that could recognize epitopes regions on the C-terminal domain, prefusion peptide, and postfusion peptide.

Every one of the four groups had antibodies that could detect the stem helix-heptad repeat 2 (SH-H) epitope region.

Groups with vaccine-induced antibodies had a stronger response towards the HR2 epitope than groups with naturally acquired antibodies.

These results further strengthen the argument that macaques are an unreliable animal model for studying SARS-CoV-2 antibody responses and translating the findings to humans.

Differences in spike protein detection

Some SARS-CoV-2 spike proteins have developed mutations that make it harder for antibodies to identify and target epitope regions. The researchers focused on the escape profiles for the C-terminal domain, fusion peptide, and SH-H epitope region.

The antibodies from vaccinated macaques, vaccinated humans, and macaques with natural immunity were successful in detecting peptides in the C-terminal domain. In contrast, antibodies from naturally acquired immunity in humans failed to recognize the epitope region. However, there was large variability in rates of detection across groups.

In the fusion peptide epitope region, antibody responses also varied. Most antibodies across all groups did not detect the AA 811-825 fusion peptide epitope region.

For the SH-H epitope region, all four groups identified peptides in the region. Moreover, antibodies across all groups failed to detect the mutated AA 1145-1158 epitope region.

*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.