Project description:Antibody responses are essential for protection against influenza virus infection. Humans are exposed to a multitude of influenza viruses throughout their lifetime and it is clear that immune history influences the magnitude and quality of the antibody response. The 'original antigenic sin' concept refers to the impact of the first influenza virus variant encounter on lifelong immunity. Although this model has been challenged since its discovery, past exposure, and likely one's first exposure, clearly affects the epitopes targeted in subsequent responses. Understanding how previous exposure to influenza virus shapes antibody responses to vaccination and infection is critical, especially with the prospect of future pandemics and for the effective development of a universal influenza vaccine.
Project description:Immunity to influenza viruses can be long-lived, but reinfections with antigenically distinct viral strains and subtypes are common. Reinfections can boost antibody responses against viral strains first encountered in childhood through a process termed "original antigenic sin." It is unknown how initial childhood exposures affect the induction of antibodies against the hemagglutinin (HA) stalk domain of influenza viruses. This is an important consideration since broadly reactive HA stalk antibodies can protect against infection, and universal vaccine platforms are being developed to induce these antibodies. Here we show that experimentally infected ferrets and naturally infected humans establish strong "immunological imprints" against HA stalk antigens first encountered during primary influenza virus infections. We found that HA stalk antibodies are surprisingly boosted upon subsequent infections with antigenically distinct influenza A virus subtypes. Paradoxically, these heterosubtypic-boosted HA stalk antibodies do not bind efficiently to the boosting influenza virus strain. Our results demonstrate that an individual's HA stalk antibody response is dependent on the specific subtype of influenza virus that they first encounter early in life. We propose that humans are susceptible to heterosubtypic influenza virus infections later in life since these viruses boost HA stalk antibodies that do not bind efficiently to the boosting antigen.
Project description:Original antigenic sin is the phenomenon in which prior exposure to an antigen leads to a subsequent suboptimal immune response to a related antigen. Immune memory normally allows for an improved and rapid response to antigens previously seen and is the mechanism by which vaccination works. I here develop a dynamical system model of the mechanism of original antigenic sin in influenza, clarifying and explaining the detailed spin-glass treatment of original antigenic sin. The dynamical system describes the viral load, the quantities of healthy and infected epithelial cells, the concentrations of naïve and memory antibodies, and the affinities of naïve and memory antibodies. I give explicit correspondences between the microscopic variables of the spin-glass model and those of the present dynamical system model. The dynamical system model reproduces the phenomenon of original antigenic sin and describes how a competition between different types of B cells compromises the overall effect of immune response. I illustrate the competition between the naïve and the memory antibodies as a function of the antigenic distance between the initial and subsequent antigens. The suboptimal immune response caused by original antigenic sin is observed when the host is exposed to an antigen which has intermediate antigenic distance to a second antigen previously recognized by the host's immune system.
Project description:Original antigenic sin is a phenomenon wherein sequential exposure to closely related influenza virus variants reduces antibody (Ab) response to novel antigenic determinants in the second strain and, consequently, impairs the development of immune memory. This could pose a risk to the development of immune memory in persons previously infected with or vaccinated against influenza. Here, we explored strategies to overcome original antigenic sin responses in mice sequentially exposed to two closely related hemagglutinin 1 neuraminidase 1 (H1N1) influenza strains A/PR/8/34 and A/FM/1/47. We found that dendritic cell-activating adjuvants [Bordetella pertussis toxin (PT) or CpG ODN or a squalene-based oil-in-water nanoemulsion (NE)], upon administration during the second viral exposure, completely protected mice from a lethal challenge and enhanced neutralizing-Ab titers against the second virus. Interestingly, PT and NE adjuvants when administered during the first immunization even prevented original antigenic sin in subsequent immunization without any adjuvants. As an alternative to using adjuvants, we also found that repeated immunization with the second viral strain relieved the effects of original antigenic sin. Taken together, our studies provide at least three ways of overcoming original antigenic sin.
Project description:BackgroundThe effects of pre-existing endemic human coronavirus (HCoV) immunity on SARS-CoV-2 serologic and clinical responses are incompletely understood.ObjectivesWe sought to determine the effects of prior exposure to HCoV Betacoronavirus HKU1 spike protein on serologic responses to SARS-CoV-2 spike protein after intramuscular administration in mice. We also sought to understand the baseline seroprevalence of HKU1 spike antibodies in healthy children and to measure their correlation with SARS-CoV-2 binding and neutralizing antibodies in children hospitalized with acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome (MIS-C).MethodsGroups of 5 mice were injected intramuscularly with two doses of alum-adjuvanted HKU1 spike followed by SARS-CoV-2 spike; or the reciprocal regimen of SARS-Cov-2 spike followed by HKU1 spike. Sera collected 21 days following each injection was analyzed for IgG antibodies to HKU1 spike, SARS-CoV-2 spike, and SARS-CoV-2 neutralization. Sera from children hospitalized with acute COVID-19, MIS-C or healthy controls (n = 14 per group) were analyzed for these same antibodies.ResultsMice primed with SARS-CoV-2 spike and boosted with HKU1 spike developed high titers of SARS-CoV-2 binding and neutralizing antibodies; however, mice primed with HKU1 spike and boosted with SARS-CoV-2 spike were unable to mount neutralizing antibodies to SARS-CoV-2. HKU1 spike antibodies were detected in all children with acute COVID-19, MIS-C, and healthy controls. Although children with MIS-C had significantly higher HKU1 spike titers than healthy children (GMT 37239 vs. 7551, P = 0.012), these titers correlated positively with both SARS-CoV-2 binding (r = 0.7577, P<0.001) and neutralizing (r = 0.6201, P = 0.001) antibodies.ConclusionsPrior murine exposure to HKU1 spike protein completely impeded the development of neutralizing antibodies to SARS-CoV-2, consistent with original antigenic sin. In contrast, the presence of HKU1 spike IgG antibodies in children with acute COVID-19 or MIS-C was not associated with diminished neutralizing antibody responses to SARS-CoV-2.
Project description:A large number of published studies have shown that adaptive immunity to a particular antigen, including pathogen-derived, can be boosted by another, cross-reacting antigen while inducing suboptimal immunity to the latter. Although this phenomenon, called original antigenic sin (OAS), was first reported approximately 70 years ago (Francis et al. 1947 Am. J. Public Health 37, 1013-1016 (doi:10.2105/AJPH.37.8.1013)), its underlying biological mechanisms are still inadequately understood (Kim et al. Proc. Natl Acad. Sci. USA 109, 13 751-13 756 (doi:10.1073/pnas.0912458109)). Here, focusing on the humoral aspects of adaptive immunity, I propose a simple and testable mechanism: that OAS occurs when T regulatory cells induced by the first antigen decrease the dose of the second antigen that is loaded by dendritic cells and available to activate naive lymphocytes. I use both a parsimonious mathematical model and experimental data to confirm the deductive validity of this proposal. This model also explains the puzzling experimental observation that administering certain dendritic cell-activating adjuvants during antigen exposure alleviates OAS. Specifically, the model predicts that such adjuvants will attenuate T regulatory suppression of naive lymphocyte activation. Together, these results suggest additional strategies for redeeming adaptive immunity from the destructive consequences of antigenic 'sin'.
Project description:We developed a DNA barcoding method to enable high-throughput sequencing of the cognate heavy- and light-chain pairs of the antibodies expressed by individual B cells. We used this approach to elucidate the plasmablast antibody response to influenza vaccination. We show that >75% of the rationally selected plasmablast antibodies bind and neutralize influenza, and that antibodies from clonal families, defined by sharing both heavy-chain VJ and light-chain VJ sequence usage, do so most effectively. Vaccine-induced heavy-chain VJ regions contained on average >20 nucleotide mutations as compared to their predicted germline gene sequences, and some vaccine-induced antibodies exhibited higher binding affinities for hemagglutinins derived from prior years' seasonal influenza as compared to their affinities for the immunization strains. Our results show that influenza vaccination induces the recall of memory B cells that express antibodies that previously underwent affinity maturation against prior years' seasonal influenza, suggesting that 'original antigenic sin' shapes the antibody response to influenza vaccination.
Project description:A number of SARS-CoV-2 variants that have evolved to have significant immune escape have emerged worldwide since the COVID-19 outbreak. The efficacy of prime vaccination is waning with the evolution of SARS-CoV-2, and the necessity of booster doses is more and more prominent. Therefore, this study aimed to compare the neutralization activity against the wild type and variants (Beta, Delta, and Omicron) in different prime-boost vaccination regimens. Electronic databases including PubMed, the Cochrane Library, Embase, medRxiv, Wanfang and CNKI were used to retrieve original studies. A total of 16 studies, 9 prime-boost vaccination regimes, and 3134 subjects were included in the meta-analysis and random effect models were used to estimate pooled neutralization titers. The neutralization activity against SARS-CoV-2 showed a significant decline with the evolution of the virus, especially in the populations primed with inactivated vaccines. For homologous immunization, only the populations boosted with mRNA vaccines consistently had a significant rise in neutralization titers (Beta: MD = 0.97; Delta: MD = 1.33; Omicron: MD = 0.74). While the heterologous immunization was more effective, the increment of neutralization titers against wild type, Beta, Delta and Omicron was 1.65 (95% CI: 1.32-1.96), 1.03 (95% CI: 0.53-1.54), 1.46 (95% CI: 1.07-1.85) and 1.15 (95% CI: 0.68-1.61), respectively. With the evolution of SARS-CoV-2, the effectiveness of prime immunization is waning. Although the administration of the booster dose could ameliorate the neutralization titers, homologous immunization regimens were gradually losing their effectiveness. Therefore, a heterologous booster dose is required, especially in populations primed with inactivated vaccines.
Project description:Human antibodies (Abs) elicited by influenza viruses often bind with a high affinity to past influenza virus strains, but paradoxically, do not bind to the viral strain actually eliciting the response. This phenomena is called 'original antigenic sin' (OAS) since this can occur at the expense of generating new de novo Abs. Here, we characterized the specificity and functionality of Abs elicited in mice that were sequentially exposed to two antigenically distinct H1N1 influenza virus strains. Many Abs elicited under these conditions had an OAS phenotype, in that they bound strongly to the viral strain used for the first exposure and very weakly to the viral strain used for the second exposure. We found that OAS and non-OAS Abs target the same general region of the influenza hemagglutinin protein and that B cells expressing these two types of Abs can be clonally-related. Surprisingly, although OAS Abs bound with very low affinities, some were able to effectively protect against an antigenically drifted viral strain following passive transfer in vivo. Taken together, our data indicate that OAS Abs share some level of cross-reactivity between priming and recall viral strains and that B cells producing these Abs can be protective when recalled into secondary immune responses.
Project description:We performed a study investigating donors previously infected with SARS-CoV-2 during the first wave of the COVID-19 pandemic to understand how vaccination may reshape T cell populations formed after infection. 10 donors were investigated using single-cell RNA-sequencing consisting of a) 3 mild non-hospitalised donors, b) 3 severe hospitalised donors, c) 1 mild recently vaccinated donor and d) 3 recently convalescent donors. For each of these groups we sampled at the following timepoints a) 6-9 months and 18 months after infection, b) 6-9 months and 18 months after infection, c) 13 months and 15 months after infection and d) 35 days after infection. All donors were unvaccinated at the first time point and vaccinated at the second time point. We stimulated PBMC with an overlapping peptide pool derived from the spike glycoprotein of the SARS-CoV-2 virus and sorted spike-specific CD4+ T cells (CD4+CD69+CD40L+) and spike-specific CD8+ T cells (CD8+CD69+4-1BB+) from every donor and time point using flow cytometry for 10X single-cell sequencing (5' protocol). Each time point from Dnr4868 was sequenced across two 10X reactions/libraries performed on the same day. Multiple samples were hashed and pooled together for sequencing using TotalSeq-C anti-human hashing antibodies from BioLegend. Individual library expression matrix files were generated using the CellRanger pipeline from 10X Genomics. The processed data file named immune.combined220929.rds is a Seurat Object containing all samples and generated using the Seurat package in R.