Anti-SARS-CoV-2 receptor-binding domain IgG titers and associated factors after heterologous mRNA booster vaccination in individuals primed with the inactivated vaccine.
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.
Abstract
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to circulate globally, highlighting the need to understand immune responses after heterologous booster vaccination. This cross-sectional study evaluated anti-SARS-CoV-2 receptor-binding domain (RBD) IgG titers and associated factors among adults who had completed a two-dose CoronaVac primary series and received a mRNA-based booster dose (BNT162b2 or mRNA-1273) 1-13 months before sampling, with no documented or self-reported history of COVID-19. Anti-SARS-CoV-2 RBD IgG was measured using the Abbott SARS-CoV-2 IgG II Quant assay. Antibody titers were ln-transformed and analyzed using independent t-tests, one-way analysis of variance, and log-linear regression, with results reported as geometric mean titers (GMTs) and geometric mean ratios (GMRs). A total of 158 participants were included. Anti-SARS-CoV-2 RBD IgG GMTs were not significantly different between the two booster groups. In the combined analysis, the highest GMT was observed in the ≤3-month post-booster interval group, followed by lower GMTs at longer intervals. After adjustment for age, sex, and body mass index, participants sampled at 4-6 months had significantly lower titers than those sampled at ≤3 months (adjusted GMR=0.42; 95%CI: 0.22-0.82). Overweight participants had higher titers than those with normal body mass index in the combined analysis (adjusted GMR=1.73; 95%CI: 1.04-2.86). These findings suggest lower humoral immune responses with increasing time after heterologous mRNA booster vaccination in individuals primed with CoronaVac and may inform future booster strategies.
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.
T. Pongrácz, U. Marking, O. Bladh et al.· Scientific Reports· 0 citations
SARS-CoV-2 has evolved into several genetic variants, all bearing mutations that reduce antibody binding and affect vaccine and treatment effectiveness. Updated COVID-19 vaccines, including bivalent formulations (wild type [WT]/BA.1 or WT/BA.5) and more recent monovalent versions targeting emerging variants such as XBB.1.5, JN.1, KP.2 or LP.8.1, were developed to broaden protection. However, immune imprinting may limit the induction of neutralizing antibodies against strains that differ significantly, even after receiving several variant-specific boosters. A deeper understanding of how booster vaccination reshapes antibody specificity remains essential for rational vaccine design. We examined the antibody response to a bivalent WT/BA.5 booster, focusing on antibody levels and neutralization. Serum samples collected before and after a fourth dose of monovalent WT or bivalent (WT/BA.5) mRNA vaccines were compared with sera from individuals after primary WT infections and Omicron BA.1, BA.2, or BA.5 breakthrough infections. We found that both monovalent and bivalent boosters significantly increased IgG and neutralizing antibodies, but breakthrough infections induced broader cross-reactive responses. Depletion experiments revealed that booster-induced immunity was predominantly mediated by cross-reactive antibodies, with the highest levels after breakthrough infections and the lowest after a primary WT infection. These findings provide functional insights into the antibody specificities associated with imprinting effects following variant-adapted booster vaccination.
Iris Medits-Weiss, Dominik Moll, D. Springer et al.· Scientific Reports· 0 citations
BACKGROUND
SARS-CoV-2-induced latent autoimmunity may play a role in long-COVID symptoms. This study explored associations between serum immunoglobulin G (IgG) responses to 18 self-antigens and antibody responses to SARS-CoV-2 and common chronic infections: Epstein-Barr virus (EBV), cytomegalovirus (CMV), Helicobacter pylori, and Toxoplasma gondii.
METHODS
This cross-sectional study used 179 SARS-CoV-2 convalescent serum samples acquired from biobanks and 123 pre-pandemic serum samples. IgG responses to SARS-CoV-2 spike, receptor binding domain, spike subunit 2, and nucleocapsid antigens were measured using an in-house Luminex multiplexed suspension fluorescence immunoassay. IgG responses to four chronic infections were quantified using commercial ELISA kits. Autoantibody responses to 18 self-antigens were simultaneously measured using a commercially available multiplexed Luminex assay; combined autoantibody reactivity was defined as the geometric mean of the 18 individual autoantibody responses.
RESULTS
Combined autoantibody reactivity and responses to several individual self-antigens were significantly higher in SARS-CoV-2 convalescent, seropositive individuals than in seronegative pre-pandemic controls. Associations between CMV, EBV, H. pylori, and T. gondii seropositivity and combined autoantibody reactivity were not statistically significant. Stronger antibody responses to antigens of the SARS-CoV-2 spike protein (S, S2, and RBD) in convalescent individuals were significantly associated with greater combined autoantibody reactivity and increased responses to multiple individual self-antigens. Conversely, antibody responses to antigens of CMV, EBV, H. pylori, and T. gondii in corresponding subsets of seropositive individuals were not associated with combined autoantibody reactivity.
CONCLUSION
SARS-CoV-2 infection and the intensity of IgG responses to the spike protein were associated with increased autoantibody reactivity, a potential indicator of latent autoimmunity.
Andrey I. Egorov, Shannon M. Griffin, Miyu Fuzawa et al.· Immunology Letters· 0 citations
Medical laboratory professionals are at higher risk of contracting COVID-19, making vaccination a critical preventive strategy. Hence, the Indonesian Government prioritized laboratory professionals for vaccination with inactivated vaccines. The immunogenicity of inactivated COVID-19 vaccines involves both humoral and cellular immune responses. This study aimed to evaluate the relationship between Anti-SARS-CoV-2 S antibody levels and cellular immune markers, including NK cells count, absolute lymphocyte count (ALC), and CD4+/CD8+ T cell ratio following COVID-19 vaccination. An observational cross-sectional study conducted at Dr. Moewardi Hospital, Indonesia, from February 2021 to October 2022. This study included 50 laboratory professionals who had received the first and second doses of the inactivated COVID-19 vaccine. A weak yet statistically significant positive correlation between NK cells count and Anti-SARS-CoV-2 S antibody (p=0.026; r=0.315) was identified. A moderate positive correlation with statistical significance was also observed between the CD4+/CD8+ ratio and the absolute number of lymphocytes with Anti-SARS-CoV-2 S antibody (p=0.002; r=0.421, and p <0.001; r=0.481), respectively. These findings indicated that the first and second doses of the inactivated vaccine stimulated humoral immune response more strongly than a cellular immune response in this population. These findings can be utilized in selecting the vaccine types for healthcare professionals to prevent potential infections from new SARS-CoV-2 variants even after the COVID-19 pandemic has been declared over.
Luhut Suryanugraha, B. R. A. Sidharta, M. D. Pramudianti et al.· INDONESIAN JOURNAL OF CLINIC...· 0 citations
The diversity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine platforms and widespread natural exposure have created a complex landscape of humoral immunity requiring detailed characterization. Here, we compare nucleocapsid (N)- and spike (S)-specific antibody responses in sera from infected humans (IH) during the first pandemic wave (April–August 2020) and in vaccine recipients (Sinopharm, Sinovac, or AstraZeneca) using commercial ELISA kits. Among naturally IH, the IgG-positivity rate was higher for N (80.9%) than S (42.8%), with significantly elevated N-specific IgG levels compared to prepandemic controls (p-value <0.05), while IgM responses showed no significant differences. Strong positive correlations were observed between S- and N-specific antibody responses, particularly for IgG and its subclasses. Vaccinated cohorts exhibited high IgG positivity rate (83–100%) against both antigens with low IgM levels, and overall IgG and subclass responses were significantly elevated relative to pre-pandemic controls (p-value <0.05), with consistently strong inter-antigen correlations across groups. Overall, natural infection induces a coordinated humoral response biased toward the nucleocapsid antigen, supporting its utility as a marker of recent infection, whereas vaccination elicits a robust multi-subclass antibody response with platform-dependent differences in antigen recognition and subclass distribution.
M. H. Nasraa, D. Abd-Elshafy, Rola Nadeem et al.· Viral immunology· 0 citations
BACKGROUND
Compared with homologous boosting, heterologous boosting with a different COVID-19 vaccine following priming generates stronger antibody responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as variants, particularly for inactivated COVID-19 vaccine(CoronaVac). However, it is still unclear about the potential immune enhancement mechanism underlying heterologous boosting.
METHODS
In this study, we isolated spike protein binding-specific monoclonal antibodies at day 180 post a homologous booster with CoronaVac or a heterologous booster with Ad5-nCoV based on two-dose of CoronaVac using the single B cell sorting platform. Subsequently, we verified their neutralization activity to SARS-CoV-2 variants, germline gene sequences and affinity kinetics targeting SARS-CoV-2 NTD/RBD/S1. Additionally, we conducted an in-depth analysis of the immunological response characteristics, by integrating single-cell RNA/V(D)J sequencing(scRNA/ V(D)J-seq).
RESULTS
Our study demonstrated that heterologous boosting with Ad5-nCoV elicited more mature B cells with higher affinity and activated more abundant immune-related pathways compared to the homologous boosting with CoronaVac. In addition, Ad5-nCoV boosting expanded unique clonal types of B and T cells, whereas CoronaVac boosting led to a small-sized clonal expansion. Furthermore, the utilization of germlines associated with neutralizing antibody were preferentially enriched in recipients with Ad5-nCoV boosting.
CONCLUSIONS
Above all, our study gives insights for elaborating the systemic immune landscape of heterologous-boosting COVID-19 immunization by the novel single B cell sorting platform and scRNA/V(D)J-seq technology.
TRIAL REGISTRATION NUMBER
NCT04892459.
Xu Han, Hudachuan Jiang, Hui Zheng et al.· Journal of Translational Med...· 0 citations
