PREreview del Pre-existing antibodies and age shape the immune response following EV-A71 vaccine: a prospective serological study among the Chinese pediatric population

Summary & Methods

This preprint illustrates the first study to model the EV-A71 vaccine, used to treat hand, foot, and mouth disease (HFMD), through the combination of pre- and post-vaccination antibody titers and age. The EV-A71 vaccine has been proven to have a high efficacy rate (over 90%), but the ways in which age and baseline antibodies affect this response is less well known. The authors used generalized additive mixed models (GAMMs) to study the link between antibody level and age and analyze vaccination responses and quantify the affect of pre-existing antibody levels in vaccine response. The study also focused on baseline titers of participants, including seropositive participants. Their research ultimately investigated the effects, if any, of pre-existing antibody titers and age at vaccination on immune responses in participants with varying pre-vaccine titer levels. 

The study population included 1585 Chinese children aged 5-36 months from both a clinical trial and a cohort study. The participants were split into three groups based on their baseline antibody levels, including high baseline antibodies, low baseline antibodies, and undetectable baseline antibodies. Using a modified cytopathogenic effect assay, researchers measured antibody levels post 2 doses of the vaccine and measured the fold increase over pre-existing baseline titer levels. They controlled for sex, vaccination age, date of sampling, and source of data. They found that the titers post 2 doses of vaccine were highest among children in the high baseline antibody group, even though their fold increase was less than children in the low or undetectable baseline antibody group. They also found that an increase in age at vaccination, when controlling for other factors, resulted in an increase in vaccine-induced antibody titers. The researchers noted that they were only focused on short-term responses to vaccination, and that extended evidence is needed. This manuscript has long-term reference, and is innovative in terms of technical novelty and future vaccination policy making. This preprint is well written and describes a thought-out experiment to test vaccination response and administration. However, their ability to improve a few issues about design choice and literature review would greatly improve the quality of the paper. 

Major Issues 

1. The methods section needs more detail and references to clarify their decision to use specific modeling types of GMTs and GMFI in their methodology. I would suggest adding literature review or references to similar vaccine studies that use the same methods to defend the usage of these modeling methods to test the efficacy and understanding of the EV-A71 vaccine is the best under these modeling methods. 

   1. This reference could be sited to provide evidence of the use of titers when investigating antibody methodology: 

      1. Miyazaki H, Yamanaka G, Furukawa K, Ichiki M. Effect of vaccine program on IgG antibody titers for measles, rubella, varicella, and mumps in young adults in Japan: Survey between 2018 and 2021. J Infect Chemother. 2022 Oct;28(10):1410-1414. doi: 10.1016/j.jiac.2022.06.016. Epub 2022 Jun 29. PMID: 35779802. 

      2. Taniguchi Y, Suemori K, Tanaka K, Okamoto A, Murakami A, Miyamoto H, Takasuka Y, Yamashita M, Takenaka K. Long-term transition of antibody titers in healthcare workers following the first to fourth doses of mRNA COVID-19 vaccine: Comparison of two automated SARS-CoV-2 immunoassays. J Infect Chemother. 2023 May;29(5):534-538. doi: 10.1016/j.jiac.2023.01.007. Epub 2023 Jan 22. Erratum in: J Infect Chemother. 2024 Nov;30(11):1197. doi: 10.1016/j.jiac.2024.05.002. PMID: 36696921; PMCID: PMC9867842. 

2. The discussion is well-written, but the authors should clarify the relationship between pre-existing antibody levels and vaccine response. For instance, the authors write that “pre-existing antibody levels may dampen the apparent antibody boosting by the EV-A71 vaccine…” I suggest that the authors address why the antibody levels may appear lower, such as a such as a ceiling effect or another sort of immunological suppression. I would recommend clarifying that this “dampening” does not necessarily imply reduced responsiveness to the vaccine, but could be a consequence of differing baseline antibody levels. If the authors were to write a few sentences about this relationship touch on this idea (whether or not they agree) in the discussion, the strength of their evidence would greatly increase. 

Minor Issues

1. The preprint’s abstract states that “vaccine-induced responses also varied with age, showing periodic increases in children under 36 months.” I would suggest that the authors explain what kind of pattern they found in vaccine-induced responses, as a “period increase” is somewhat vague. How was this pattern increase measured, for instance, and was this increase graduate, cyclical, random, etc? This would help the readers understand further how age and vaccine response are related. 

Competing interests

The authors declare that they have no competing interests.

Use of Artificial Intelligence (AI)

The authors declare that they did not use generative AI to come up with new ideas for their review.