Review 1: "Comprehensive Antibody Profiling of mRNA Vaccination in Children"

Ermelinda Porpiglia

doi:doi:10.1162/2e3983f5.86b4947d

Comprehensive antibody profiling of mRNA vaccination in children

by Yannic C Bartsch, Kerri J St Denis, Paulina Kaplonek, Jaewon Kang, Evan C. Lam, Madeleine D Burns, Eva J Farkas, Jameson P Davis, Brittany P Boribong, Andrea G Edlow, Alessio Fasano, Wayne Shreffler, Dace Zavadska, Marina Johnson, David Goldblatt, Alejandro B Balazs, Lael M Yonker, and Galit Alter

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Description

AbstractWhile children have been largely spared from COVID-19 disease, the emergence of viral variants of concern (VOC) with increased transmissibility, combined with fluctuating mask mandates and school re-openings have led to increased infections and disease among children. Thus, there is an urgent need to roll out COVID-19 vaccines to children of all ages. However, whether children respond equivalently to adults to mRNA vaccines and whether dosing will elicit optimal immunity remains unclear. Given the recent announcement of incomplete immunity induced by the pediatric dose of the BNT162b2 vaccine in young children, here we aimed to deeply profile and compare the vaccine-induced humoral immune response in 6-11 year old children receiving the pediatric (50μg) or adult (100μg) dose of the mRNA-1273 vaccine compared to adults and naturally infected children or children that experienced multi inflammatory syndrome in children (MIS-C) for the first time. Children elicited an IgG dominant vaccine induced immune response, surpassing adults at a matched 100μg dose, but more variable immunity at a 50μg dose. Irrespective of titer, children generated antibodies with enhanced Fc-receptor binding capacity. Moreover, like adults, children generated cross-VOC humoral immunity, marked by a decline of omicron receptor binding domain-binding, but robustly preserved omicron Spike-receptor binding, with robustly preserved Fc-receptor binding capabilities, in a dose dependent manner. These data indicate that while both 50μg and 100μg of mRNA vaccination in children elicits robust cross-VOC antibody responses, 100ug of mRNA in children results in highly preserved omicron-specific functional humoral immunity.One-Sentence SummarymRNA vaccination elicits robust humoral immune responses to SARS-CoV-2 in children 6-11 years of age.

RR:C19 Evidence Scale rating by reviewer:

Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

Summary

COVID-19 is a severe respiratory disease caused by the novel coronavirus SARS-CoV-2. Without vaccination, children constitute a potential reservoir of SARS-CoV-2 infections, given their lack of symptoms and high viral load. This manuscript addresses two very relevant questions in the midst of the pandemic: do young children mount an effective antibody response to COVID-19 mRNA vaccines? Is the antibody response induced by the vaccine effective against SARS-CoV-2 variants of concern, such as the delta variant? The authors performed a deep analysis of the antibody response to the mRNA-1273 Moderna vaccine in 7-11 years old children and compared their response to the antibody response in unvaccinated children that were naturally infected with SARS-CoV-2, children that developed the life-threatening Multisystem Inflammatory Syndrome (MIS-C) and vaccinated adults. Using Luminex Assays to measure antibody titers and antibody-dependent functional assays, they found an increase in antibody titers and function in fully vaccinated children compared to unvaccinated naturally infected children. Moreover, they found that vaccination in children elicits a more robust antibody response to variants of concerns, such as the delta variant, compared to natural infection in children. Finally, they uncovered unique differences in the antibody response between vaccinated children and adults. The authors conclude that mRNA-1273 Moderna vaccine induces robust antibody responses to the wild type SARS-CoV-2 virus and the delta variant in children, and improves antibody dependent effector functions.

Critique

The study is well designed and performed and the data support the conclusions. One limitation of the study is the small number of participants for each cohort. However, the results presented are statistically significant and the authors performed the appropriate statistical tests to prevent false positives. Moreover, in the discussion the authors acknowledge the need for larger cohorts in order to gain key insights into the differences in antibody response between vaccinated children and adults.
The heatmap in Figure 2E is unclear, due to the multiple parameters being analyzed simultaneously in children and adults. A side-by-side comparison of the individual parameters in children and adults would be clearer.
When referring to Figure 3, a more detailed explanation of the machine learning model (A) and the co-correlation network (B) used would add clarity for readers who are unfamiliar with modeling.
Given the importance of comparing the functional antibody response to the SARS-CoV-2 delta variant between vaccinated children and unvaccinated naturally infected children, the data presented in Supplementary Figure 4 should be moved to Figure 4.