Antibody avidity, persistence, and response to antigen recall: comparison of vaccine adjuvants.
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ABSTRACT:
SUBMITTER: Budroni S
PROVIDER: S-EPMC8140094 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Seasonal influenza vaccines represent a positive intervention to limit the spread of the virus and protect public health. Yet continual influenza evolution and its ability to evade immunity pose a constant threat. For these reasons, vaccines with improved potency and breadth of protection remain an important need. We previously developed a next-generation influenza vaccine that displays the trimeric influenza hemagglutinin (HA) on a ferritin nanoparticle (NP) to optimize its presentation. Similar to other vaccines, HA-nanoparticle vaccine efficacy is increased by the inclusion of adjuvants during immunization. To identify the optimal adjuvants to enhance influenza immunity, we systematically analyzed TLR agonists for their ability to elicit immune responses. HA-NPs were compatible with nearly all adjuvants tested, including TLR2, TLR4, TLR7/8, and TLR9 agonists, squalene oil-in-water mixtures, and STING agonists. In addition, we chemically conjugated TLR7/8 and TLR9 ligands directly to the HA-ferritin nanoparticle. These TLR agonist-conjugated nanoparticles induced stronger antibody responses than nanoparticles alone, which allowed the use of a 5000-fold-lower dose of adjuvant than traditional admixtures. One candidate, the oil-in-water adjuvant AF03, was also tested in non-human primates and showed strong induction of neutralizing responses against both matched and heterologous H1N1 viruses. These data suggest that AF03, along with certain TLR agonists, enhance strong neutralizing antibody responses following influenza vaccination and may improve the breadth, potency, and ultimately vaccine protection in humans.
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Project description:The HPV vaccine has shown sustained efficacy and consistent stabilization of antibody levels, even after a single dose. We defined the HPV16-VLP antibody avidity patterns over 11 years among women who received one- or three doses of the bivalent HPV vaccine in the Costa Rica HPV Vaccine Trial. Absolute HPV16 avidity was lower in women who received one compared to three doses, although the patterns were similar (increased in years 2 and 3 and remained stable over the remaining 8 years). HPV16 avidity among women who were HPV16-seropositive women at HPV vaccination, a marker of natural immune response to HPV16 infection, was significantly lower than those of HPV16-seronegative women, a difference that was more pronounced among one-dose recipients. No differences in HPV16 avidity were observed by HPV18 serostatus at vaccination, confirming the specificity of the findings. Importantly, point estimates for vaccine efficacy against incident, six-month persistent HPV16 infections was similar between women who were HPV16 seronegative and seropositive at the time of initial HPV vaccination for both one-dose and three-dose participants. It is therefore likely that this lower avidity level is still sufficient to enable antibody-mediated protection. It is encouraging for long-term HPV-vaccine protection that HPV16 antibody avidity was maintained for over a decade, even after a single dose.
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Project description:Aluminum salts and squalene based oil-in-water emulsions (SE) are widely used adjuvants in licensed vaccines, yet their mechanisms are not fully known. Here we report that induction of antibody responses displays different kinetics dependent on the adjuvant used. SE facilitated a rapid antibody response in contrast to aluminum hydroxide (AH) and the depot-forming cationic liposome-based adjuvant (CAF01). Antigen given with the SE adjuvant rapidly reached follicular B cells in the draining lymph node, whereas antigen formulated in AH or CAF01 remained at the site of injection as a depot. Removal of the injection site early after immunization abrogated antibody responses only when antigen was given in the depot-forming adjuvants. Despite initial delays in B cell activation and germinal center (GC) formation when antigen was given in depot-forming adjuvants, the antibody levels reached higher magnitudes than when the antigen was formulated in SE. This study demonstrates that the kinetic aspect of antibody responses is critical in adjuvant benchmarking and suggests that the optimal vaccination regime depends on the adjuvant used.
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Project description:Adjuvants contribute to enhancing and shaping the vaccine immune response through different modes of action. Here early biomarkers of adjuvanticity after primary immunization were investigated using four different adjuvants combined with the chimeric tuberculosis vaccine antigen H56. C57BL/6 mice were immunized by the subcutaneous route with different vaccine formulations, and the modulation of primary CD4+ T cell and B cell responses was assessed within draining lymph nodes, blood, and spleen, 7 and 12 days after priming. Vaccine formulations containing the liposome system CAF01 or a squalene-based oil-in-water emulsion (o/w squalene), but not aluminum hydroxide (alum) or CpG ODN 1826, elicited a significant primary antigen-specific CD4+ T cell response compared to antigen alone, 7 days after immunization. The effector function of activated CD4+ T cells was skewed toward a Th1/Th17 response by CAF01, while a Th1/Th2 response was elicited by o/w squalene. Differentiation of B cells in short-lived plasma cells, and subsequent early H56-specific IgG secretion, was observed in mice immunized with o/w squalene or CpG adjuvants. Tested adjuvants promoted the germinal center reaction with different magnitude. These results show that the immunological activity of different adjuvants can be characterized by profiling early immunization biomarkers after primary immunization. These data and this approach could give an important contribution to the rational development of heterologous prime-boost vaccine immunization protocols.
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Project description:Immunoglobulin G (IgG) antibodies are widely used for diagnosis and therapy. Given the unique dimeric structure of IgG, we hypothesized that, by genetically fusing a homodimeric protein (catenator) to the C-terminus of IgG, reversible catenation of antibody molecules could be induced on a surface where target antigen molecules are abundant, and that it could be an effective way to greatly enhance the antigen-binding avidity. A thermodynamic simulation showed that quite low homodimerization affinity of a catenator, e.g. dissociation constant of 100 μM, can enhance nanomolar antigen-binding avidity to a picomolar level, and that the fold enhancement sharply depends on the density of the antigen. In a proof-of-concept experiment where antigen molecules are immobilized on a biosensor tip, the C-terminal fusion of a pair of weakly homodimerizing proteins to three different antibodies enhanced the antigen-binding avidity by at least 110 or 304 folds from the intrinsic binding avidity. Compared with the mother antibody, Obinutuzumab(Y101L) which targets CD20, the same antibody with fused catenators exhibited significantly enhanced binding to SU-DHL5 cells. Together, the homodimerization-induced antibody catenation would be a new powerful approach to improve antibody applications, including the detection of scarce biomarkers and targeted anticancer therapies.
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Project description:Novel vaccine strategies include the so-called subunit vaccines, which encompass only the part of the pathogen to which immune recognition results in protection. The high purity of these vaccines make adverse events less likely, but it also makes the vaccines less immunogenic and therefore potentially less effective. Vaccine adjuvants that increase and modulate the immunogenicity of the vaccine are therefore added to solve this problem. Besides aluminum salts, which have been used in vaccines for 90 years, a number of novel vaccine adjuvants have been included in licensed vaccines over the last 30 years. Increasing insight into immunological mechanisms and how to manipulate them has replaced empirical with rational design of adjuvants, leading to vaccine adjuvants with increased and customized immunogenicity profiles without compromising vaccine safety.
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Project description:The receptor binding domain (RBD) of the SARS-CoV-2 spike protein is the primary target of neutralizing antibodies and is a component of almost all current vaccines. Here, RBD immunogens were created with stabilizing amino acid changes that improve the neutralizing antibody response, as well as characteristics for production, storage, and distribution. A computational design and in vitro screening platform identified three improved immunogens, each with approximately nine amino acid changes relative to the native RBD sequence, and four key changes conserved between immunogens. The changes are adaptable to all vaccine platforms and compatible with mutations in emerging variants of concern. The immunogens elicit higher levels of neutralizing antibodies than native RBD, focus the immune response to structured neutralizing epitopes, and have increased production yields and thermostability. Incorporating these variant-independent amino acid changes in next-generation COVID vaccines may enhance the neutralizing antibody response and lead to longer duration and broader protection.
| S-EPMC9473567 | biostudies-literature
Project description:Vaccines are critical in the fight against infectious diseases, and immune-stimulating adjuvants are essential for enhancing vaccine efficacy. However, the precise mechanisms of action of most adjuvants are unknown. There is an urgent need for customized and adjuvant formulated vaccines against immune evading pathogens that remain a risk today. Understanding the specific role of various cell types in adjuvant-induced protective immune responses is vital for an effective vaccine design. We have investigated the role of cell-specific MyD88 signaling in vaccine adjuvant activity in vivo, using Neisserial porin B (PorB), a TLR2 ligand-based adjuvant, compared with an endosomal TLR9 ligand (CpG) and toll-like receptor (TLR)-independent (alum, MF59) adjuvants. We found that intact MyD88 signaling is essential, separately, in all three antigen-presenting cell types [B cells, macrophages, and dendritic cells (DCs)] for optimal TLR ligand-based adjuvant activity. The role of MyD88 signaling in B cell and DC in vaccine adjuvant has been previously investigated. In this study, we now demonstrate that the immune response was also reduced in mice with macrophage-specific MyD88 deletion (Mac-MyD88-/-). We demonstrate that TLR-dependent adjuvants are potent inducers of germinal center (GC) responses, but GCs are nearly absent in Mac-MyD88-/- mice following immunization with TLR-dependent adjuvants PorB or CpG, but not with TLR-independent adjuvants MF59 or alum. Our findings reveal a unique and here-to-for unrecognized importance of intact MyD88 signaling in macrophages, to allow for a robust vaccine-induced immune responses when TLR ligand-based adjuvants are used.
| S-EPMC5334362 | biostudies-literature
Project description:BackgroundChAdOx1 and BNT162b2 vaccines are currently commonly used against coronavirus disease 2019 worldwide. Our study was designed to determine the serostatus and relative levels of anti-S and neutralizing antibodies in patients who were administered either ChAdOx1 or BNT162b2 vaccine. In addition, we investigated whether the antibody response to each vaccine differed according to sex and age.MethodsHealthcare workers (HCWs) at a general hospital who were vaccinated with two doses of either ChAdOx1 or BNT162b2 were invited to participate in this prospective cohort study. Blood samples of HCWs vaccinated with both ChAdOx1 doses over a period of 12 weeks were collected at weeks 4 and 8 post first vaccination and 2 weeks post second vaccination. Blood samples of HCWs vaccinated with BNT162b2 were collected in the third week after the first dose, and the second dose was then administered on the same day; two weeks post second dose (5 weeks after the first dose), blood samples were collected to assess the antibody response. The titers of anti-S antibodies against the severe acute respiratory syndrome coronavirus 2 spike (S) protein receptor-binding domain and the neutralizing antibodies in the collected blood were evaluated.ResultsOf the 309 HCWs enrolled in the study, 205 received ChAdOx1 and 104 received BNT162b2. Blood samples from participants receiving either the ChAdOx1 or BNT162b2 vaccine exhibited substantial anti-S and neutralizing antibody seropositivity subsequent to the second dose. All participants (100%) from both vaccine groups were seropositive for anti-S antibody, while 98% (201/205) of ChAdOx1-vaccinated individuals and 100% (104/104) of BNT162b2-vaccinated individuals were seropositive for neutralizing antibodies. The median levels of anti-S and neutralizing antibodies were significantly higher in the BNT162b2-vaccinated group than the ChAdOx1-vaccinated group; in particular, anti-S antibody titers of 1,020 (interquartile range, 571.0-1,631.0) U/mL vs. 2,360 (1,243-2,500) U/mL, P < 0.05, were recorded for the ChAdOx1 and BNT162b2 groups, respectively, and neutralizing antibody titers of 85.0 (65.9-92.1%) vs. 95.8 (94.4-96.6%), P < 0.05, were recorded for the ChAdOx1 and BNT162b2 groups, respectively. In the ChAdOx1 vaccine group, the neutralizing antibody level was significantly higher in women than in men (85.7 [70.3-92.5%] vs. 77.7 [59.2-91.0%], P < 0.05); however, the neutralizing antibody titer in the BNT162b2 vaccine group did not vary between the two sexes (95.9 [95.2-96.6%] vs. 95.2 [93.5-96.3%], P = 0.200). Analysis of the correlation of antibody profiles with age revealed that the levels of anti-S antibodies and signal inhibition rate (SIR) of neutralizing antibodies decreased significantly with age.ConclusionBoth the ChAdOx1- and BNT162b2-vaccinated groups showed high seropositivity for anti-S and neutralizing antibodies. The SIR of neutralizing antibodies in the ChAdOx1 vaccine group was higher in women than in men. Enhanced antibody responses were observed in participants vaccinated with BNT162b2 compared to those vaccinated with the ChAdOx1 vaccine.
| S-EPMC8629719 | biostudies-literature
Project description:The quadrivalent HPV vaccine (4vHPV) was originally recommended as a three-dose series (0/2/6 months), though delays in completing the series frequently occur. We previously found delayed dosing in girls resulted in similar or higher antibody titers compared to on-time dosing. Archived sera from 262 healthy females aged 9-18 recruited from pediatric clinics were tested to determine if delayed dosing intervals affected antibody avidity. Avidity index (AI; ratio of IgG Ab bound in the treated and untreated sample) was determined pre- and post-dose 3 4vHPV for each participant using a modified multiplex ELISA. Data were grouped by dosing intervals: (1) on-time dose 2 and 3, (2) delayed dose 2 and on-time dose 3, (3) on-time dose 2 and delayed dose 3, (4) delayed dose 2 and 3. Overall, mean AI was highest for HPV16 and lowest for HPV6. As expected, AI did not differ between groups 1 & 3 or groups 2 & 4 pre-dose 3, however, for most types mean AI was significantly higher both pre- and post-dose 3 for groups with delayed dose 2. For all types, mean AI was higher post-dose 3 in all delayed dosing groups compared to group 1. One month post-dose 3, there was a positive but weak correlation between AIs and antibody titer for HPV 6 (ρ = 0.25, p = .0001), HPV 11 (ρ = 0.14, p = .0370), HPV 16 (ρ = 0.11, p = .0934), and HPV 18 (ρ = 0.37, p < .0001). Our findings suggest longer intervals between doses result in higher antibody avidity, providing further evidence that delayed dosing of 4vHPV does not hinder the immune response.
| S-EPMC7482794 | biostudies-literature