Aug 2026· Scientific Reports· Vol 16· 0 citations· 70 references
Medicine
TL;DR
The results illustrate an IgG4-dominated immunological signature in both adults and children and highlight that immune priming by prior infection may shape subsequent mRNA vaccine-induced antibody responses.
Abstract
Repeated administration of mRNA vaccines against SARS-CoV-2 has been associated with qualitative changes in antibody responses, including the emergence of non-inflammatory IgG4 subclasses and changes in Fc glycosylation. While neutralizing antibody titers remain key correlates of protection, potential functional implications of these structural antibody features warrant further investigation across age groups and multiple mRNA vaccine boosters. We characterized spike-specific IgG responses—including subclasses and Fc glycosylation patterns—using a liquid chromatography—mass spectrometry-based approach across six mRNA vaccine doses in a Swedish healthcare worker cohort (n = 104) and across three mRNA doses in a Singaporean pediatric cohort (n = 18). Repeated mRNA vaccination induced an IgG4 class switch which was sustained across at least six doses. This response associated with an increased risk of breakthrough infection (HR = 1.83, p = 0.028) in infection-naïve individuals (n = 41) lacking mucosal IgA responses that would potentially confound the interpretation of systemic IgG4‑related infection outcomes. Moreover, the IgG4 class switch was preceded with high early IgG1 Fc fucosylation signatures. Notably, these IgG structural changes were observed primarily in individuals who were naïve to SARS-CoV-2 at the time of first vaccination. Similar IgG structural features were observed across three mRNA doses in the small infection-naive pediatric cohort. Our results illustrate an IgG4-dominated immunological signature in both adults and children and highlight that immune priming by prior infection may shape subsequent mRNA vaccine-induced antibody responses. While these findings do not call into question the efficacy or safety of the widely adapted mRNA vaccine platform, they may have implications that merit further investigation.
Lower humoral immune responses with increasing time after heterologous mRNA booster vaccination in individuals primed with CoronaVac and may inform future booster strategies are suggested.
H. Harapan, A. P. Ayulinda, Qatrunnada Kamil et al.· Acta Tropica· 0 citations
Results demonstrate that AZD6563, at reduced doses, matches the cellular immunogenicity of BNT162b2 while enhancing B cell cross-reactivity and TCR diversity in older adults, supporting its potential as a next-generation COVID-19 vaccine candidate.
Michael D. Powell, Nicholas G. Battaglia, Lee-Jah Chang et al.· Journal of Immunology· 0 citations
SARS-CoV-2 mRNA vaccines elicit robust T cell responses in children, resulting in substantial protection against hospitalisation and severe disease. However, the underlying molecular mechanisms that drive this robust cellular immunogenicity of mRNA vaccines in children remains unknown. Here, 37 immunological naïve children underwent primary vaccination (age 6-10) with the SARS-CoV-2 mRNA vaccine and did not acquire natural infection before month 3; bulk RNA sequencing was performed at pre-vaccination baseline and day 1 post vaccination, and Spike-reactive T cell responses were measured at 3 months. Using previously established threshold of T cell responses for clinical protection against symptomatic SARS-CoV-2, we divided our cohort into high responders (n = 21) and low responders (n = 15). Analyses of day 1 post-vaccination gene expression signatures revealed greater induction of innate immune responses, including heightened expression of transcription factors such as STAT1, ATF3 and IRF7 was observed in low responders compared to high responders. On the other hand, LEP, PLCE1 and PLPP2 expression was significantly downregulated in low responders, with strong predictive value for T cell responses at 3 months post-vaccination (AUROC 0.89, 95% CI 0.78-1.00). Taken together, these findings suggest that future mRNA vaccine design and vaccination regimens should aim to modulate excessive innate immune responses to improve T cell responses to mRNA vaccines.
C. Tay, Clara W. T. Koh, Justin S. G. Ooi et al.· Vaccine· 0 citations
The development and deployment of mRNA vaccines during the COVID-19 pandemic was a landmark achievement in modern medicine and ushered in a new age of vaccine innovation. The vaccines strongly elicited both neutralizing and non-neutralizing antibody responses against the viral Spike protein, but these waned over time. Self-amplifying mRNA (sa-mRNA) vaccines such as ARCT-154 can prolong antigen production and durability of humoral immune response post-immunization and can thus be administered at a lower dose. How this translates into the overall humoral architecture compared to that shaped by conventional mRNA vaccinations is unclear.
We analyzed serum antibody responses from a Phase III trial comparing humoral responses elicited by ARCT-154 and mRNA BNT162B2 by systems serology. All participants had received three doses of mRNA COVID-19 vaccines and were randomized to receive a booster dose of ARCT-154 or BNT162B2. Primary outcomes were to quantify waning responses against ancestral SARS-CoV-2 Spike and a panel of antigenically drifted SARS-CoV-2 variant Spikes.
We identified that the sa-mRNA vaccine ARCT-154 elicited a unique antibody response compared to BNT162B2 defined by a sustained, activating profile to the vaccine-encoded Spike protein and a broad spectrum of drifted Spikes. Notably, potently activating FcgRIIIA-binding antibodies showed a sustained stimulation in the ARCT-154-treatment arm, and this translated to enhanced antibody-dependent natural killer cell activation (ADNKA) to both target WT Spike and the antigenically drifted BA.5 Spike, which was the predominant form of SARS-CoV-2 during the observation period.
Recipients of the sa-mRNA booster showed a temporally sustained humoral activation and an overall antibody architecture that favored pro-activating phenotypes. Our results support a model whereby prolonged antigen expression and presentation moves immune profiles towards activating phenotypes with broad antigenic coverage.
Bill and Melinda Gates Foundation INV-080712
Vaccines and Immunotherapy (VAC)
Kate S. Levine, Ross Blanc, Qixin Wang et al.· Journal of Immunology· 0 citations
Intranasal boosting promotes greater variant-specific response at both the serum and cellular levels than i.m.n. boosting, and ongoing B cell repertoire and mAb analyses will provide mechanistic insight into how vaccination route reshapes clonal selection and maturation, informing rational vaccination design.
Xinyi Liu, Chieh-Yu Liang, Michael S. Diamond· Journal of Immunology· 0 citations
Data on immune responses to COVID-19 vaccination in West and Central Africa remain limited, particularly across SARS-CoV-2 variants and vaccine platforms. Using the InVITE cohort in the Democratic Republic of Congo, Guinea, Liberia, and Mali, we evaluated anti-spike (anti-S) antibody binding to nine SARS-CoV-2 variants in 96 participants equally selected from pre-vaccination assay defined seropositive and seronegative groups. Participants received mRNA, adenovirus-vectored, or inactivated virus vaccines. Anti-S binding was measured before vaccination and two months after completion of the primary series using a Meso Scale Discovery 10-plex assay. Before vaccination, antibody binding was significantly higher against pre-Omicron variants (Ancestral, Alpha, Beta, and Delta) than Omicron variants in both seronegative (fold change [FC] 3.85, 99% CI 3.45–4.17) and seropositive (FC 3.57, 99% CI 3.33–3.84) participants. Seropositive individuals showed greater binding than seronegative individuals across all variants. Two months post-vaccination, mRNA vaccines elicited higher antibody binding than adenovirus-vectored or inactivated vaccines, whereas no significant differences were observed between adenovirus-vectored and inactivated vaccines. Antibody binding remained higher against pre-Omicron than Omicron variants across all vaccine platforms and serostatus groups. These findings provide rare data on variant-specific vaccine-elicited antibody binding responses in West and Central African populations with distinct demographic, epidemiologic, and immunologic background.
Trial registration: Registration ClinicalTrials.gov: NCT05096091, Registration date: 10-26-2021, Clinical trial registry:
https://clinicaltrials.gov/study/NCT05096091?term=NCT05096091rank=1#study-overview
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E. Lusamaki, Ana M. Ortega-Villa, Daouda Camara et al.· Scientific Reports· 0 citations
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