“Antibody responses to viral infection often differ between infants and older individuals; however, there is still a lot to learn about how and why an infant’s immune system responds differently to infections,” explained Dr. Caitlin Stoddard, a postdoctoral researcher in the labs of Drs. Julie Overbaugh and Dara Lehman. “Our lab has studied this in the context of HIV for many years, and we hypothesized there might be unique features of the infant antibody response to SARS-CoV-2 infection,” Dr. Stoddard added. In a study recently published in Nature Communications led by Stoddard, researchers sought to understand the unique characteristics of infant viral immunity to SARS-CoV-2 infection through directly comparing the immune response between infants and their mothers. The findings from this study highlight age-related differences in immunity, showing how “antibody responses to viral infection can be highly divergent in infants versus older individuals, and can include unique binding and functional properties,” the authors stated.
To investigate age-related immune responses, the researchers focused their study on the Linda Kizazi Study cohort, which was established in Nairobi, Kenya and “offered a unique opportunity to study the antibody response in infants and compare it directly to mothers within a single cohort,” Stoddard explained. She added, “the Linda Kizazi cohort was established just prior to the emergence of SARS-CoV-2, and was originally designed as a prospective cohort study of mother-to-child virome transmission in Nairobi, Kenya. Pregnant women in their third trimester were recruited to the study and subsequently followed together with their infant for two years postpartum.” Although not initially established for the study of SARS-CoV-2, fortuitous timing of this cohort’s formation allowed them to expand their initial research study to include this new virus. “Once SARS-CoV-2 emerged and prior to vaccine availability, participants gave written informed consent for serological testing for infection with SARS-CoV-2, and from there we developed a sub-study based on seropositive samples from that testing that became the focus of this paper,” Stoddard stated.
During study follow-up serum was collected from participants about every 3 months. This enabled a powerful longitudinal study of immune responses, pre- and post- SARS-CoV-2 infection. The researchers first asked if the antibodies produced in response to infection differed between infants and their mothers. The Overbaugh and Lehman research team measured levels of IgG antibodies to the Spike protein, a protein found on the virus’ surface which is the main site recognized by antibodies. Interestingly, the authors found significantly higher antibody levels, or titers, against SARS-CoV-2 Spike protein in infants compared to mothers. They then asked if where the antibodies bound to Spike was similar or different across these groups. The two dominant antibody binding sites in both infants and mothers were to the stem helix portion and fusion peptide of the Spike protein, which helps viruses enter and infect host cells. However, the researchers found that the magnitude of these antibody responses differed between infants and mothers: infants had significantly higher levels of antibodies that recognized the fusion peptide compared to mothers. To functionally test the impact of SARS-CoV-2 mutations on the immune response in infants and mothers in this cohort, the authors utilized a deep mutational scanning (DMS) approach. Using a phage-DMS library allowed the research team to assess the impact of Spike protein mutations on antibody binding in infants and mothers. Here, they sought to identify mutations that enabled escape from antibody binding which would allow the virus to slide past the immune system’s surveillance system. The researchers analyzed the escape profile of infants and their mothers and found that infants had highly consistent escape profiles where a core set of mutations led to antibody binding escape. In contrast, comparison between individual mothers showed more variability in escape profiles, suggesting “that the infant antibody repertoire is functionally unique from that of their mothers,” Stoddard stated.
Finding differences in antibody titers, antibody affinity and escape profiles between infants and mothers, the research team wanted to understand the functional consequence of these differences on immune responses. Stoddard explained that “antibodies can have different functional activity and we most often hear about neutralizing activity—when an antibody binds to the surface of a virus and blocks its ability to bind or enter a cell. Some antibodies have other, non-neutralizing powers—for example, they can bind to infected cells and recruit effector cells to kill the infected cell (this particular activity is known as antibody-dependent cellular cytotoxicity, or ADCC). The combined efforts of neutralizing and non-neutralizing antibodies dictate antibody-mediated immunity in an infected person.” Stoddard and the research team then experimentally tested plasma from mothers and infants in a Spike-psuedotyped lentiviral neutralization assay. They found no significant difference in neutralization titer between mothers and infants, suggesting that the higher Spike antibody titers found in infants do not directly correlate to higher levels of neutralization. The researchers then asked if there was a difference in non-neutralizing ADCC activity and found that infants had significantly higher levels of ADCC activity compared to mothers. Stoddard exclaimed, “we were excited to find that infants develop higher levels of ADCC activity, and were surprised this did not translate to higher levels of neutralizing activity, despite higher levels of Spike antibody binding in infants.” Additionally, “our work suggests ADCC activity could play a role in age-related differences in SARS-CoV-2 pathogenesis and emphasizes the need to account for ADCC activity in the development of vaccines and therapeutics.”
These results highlight the unique immune responses infants have to viral infections. As to why this might be, Stoddard explained that “prior to birth, infants rely heavily on the maternal immune system for protection from infection. When born, the infant antibody response is in a unique state; immune cells in the infant are at different levels than in adults, and the infant has had very limited direct exposure to infection, precluding the development of pathogen-specific antibodies. These features—the phase of development of the infant immune system and the limited pathogenic exposures—shape the infant antibody response and are likely explanations for differences seen in infants versus adults.” She added, “There are certain themes emerging from this study and prior studies of infant antibody responses to viral infection, including remarkable functional activities in infants. For example, our lab previously discovered that infants can generate broadly neutralizing antibodies against HIV-1 more rapidly than adults. The present study also uncovered a convergent pathway of escape for infant antibodies that target the SARS-CoV-2 fusion peptide. This result bears similarity to previous work showing that infant antibodies to RSV have limited somatic mutation and convergent sequence features. So, while it remains to be seen if our findings are predictive of responses to other infections, results from this and existing studies emphasize the importance of studying antibody responses in infants, and especially highlight the importance of direct comparisons to adults, which are often limited.” The authors concluded with acknowledging the “the Linda Kizazi Study cohort participants and the Linda Kizazi Study team, including physicians, nurses, and researchers in Nairobi,” for without these contributions, “these studies would not have been possible.”
This work was supported by the National Institutes of Health, the Howard Hughes Medical Institute, the Canadian Institutes of Health Research and the Canada Foundation for Innovation.
UW/Fred Hutch/Seattle Children’s Cancer Consortium members Drs. Julie Overbaugh and Frederick Matsen contributed to this work.
Stoddard CI, Sung K, Yaffe ZA, Weight H, Beaudoin-Bussières G, Galloway J, Gantt S, Adhiambo J, Begnel ER, Ojee E, Slyker J, Wamalwa D, Kinuthia J, Finzi A, Matsen FA 4th, Lehman DA, Overbaugh J. Elevated binding and functional antibody responses to SARS-CoV-2 in infants versus mothers. Nat Commun. 2023 Aug 11;14(1):4864. doi: 10.1038/s41467-023-40554-w. PMID: 37567924; PMCID: PMC10421871.