Magnitude Of Antibody Response Research Articles

Impact of Vaccination Time on Anti-SARS-CoV-2 Antibody Levels in Adults: A Quasi-experimental Study.

Vaccination time may provide an opportunity to advance immunogenicity in terms of the immune system's circadian nature. This analytical study was planned to determine the impact of forenoon and afternoon administration of the COVID-19 vaccine to adults on the magnitude of antibody response. A total of 33 healthy adults with no history of COVID-19 infection or any other disease participated in the study. They were allotted a forenoon (900-1200 hours) or afternoon (1200-500 hours) slot for vaccination. They were categorized as a forenoon or afternoon group, with 16 subjects in the forenoon and 17 in the afternoon group. With the consent of the participants, a blood sample was collected before vaccination, 30 days after the firstand 30 days after the second dose of vaccination from all the subjects. The antibody titer response was measured using a commercial semi-quantitative assay, SARS-CoV-2 IgG II. The baseline antibody titer against COVID-19 was 51.41 ± 22.22 AU/mL and 53.21 ± 15.67 AU/mLin the forenoon and afternoon groups, respectively, which increased to15773.00 ± 3231.41 AU/mL and 12970.82 ± 7608.00 AU/mL after 30 days of the first dose of the COVID-19 vaccine in the forenoon and afternoon groups, respectively. This further increased to37007.00 ± 1697.75 AU/mL and 38012.00 ± 14001.16 AU/mL after 30 days of the second dose of the COVID-19 vaccine in the forenoon and afternoon groups, respectively. There was no difference in antibody response in subjects with forenoon and afternoon vaccinations. There was no significant difference in antibody titer in males vs. females. The study reported that antibody titers decreased with increasing age and BMI of participants. The time of the day of vaccination does not impact the immune response to COVID-19, but age and BMI are important factors to consider during vaccination against SARS-CoV-2 in the adult population.

Longitudinal analysis of memory Tfh cells and antibody response following CoronaVac vaccination.

The inactivated vaccine CoronaVac is one of the most widely used COVID-19 vaccines globally. However, the longitudinal evolution of the immune response induced by CoronaVac remains elusive compared with other vaccine platforms. Here, we recruited 88 healthy individuals who received 3 doses of CoronaVac vaccine. We longitudinally evaluated their polyclonal and antigen-specific CD4+ T cells and neutralizing antibody response after receiving each dose of vaccine for over 300 days. Both the second and third doses of vaccine induced robust spike-specific neutralizing antibodies, with a third vaccine further increasing the overall magnitude of antibody response and neutralization against Omicron sublineages B.1.1.529, BA.2, BA.4/BA.5, and BA.2.75.2. Spike-specific CD4+ T cells and circulating T follicular helper (cTfh) cells were markedly increased by the second and third dose of CoronaVac vaccine, accompanied by altered composition of functional cTfh cell subsets with distinct effector and memory potential. Additionally, cTfh cells were positively correlated with neutralizing antibody titers. Our results suggest that CoronaVac vaccine-induced spike-specific T cells are capable of supporting humoral immunity for long-term immune protection.

1102. The Host Response to SARS-CoV-2 Infection Differs by Age

Abstract Background Infection with SARS-CoV-2 and the resulting host immune response has been primarily characterized in middle and older aged populations due to a higher incidence of symptoms in these age groups. Due to reduced severity of disease, children were poorly studied and assumed to be less frequently infected compared to older age groups. We measured the viral load and adaptive immune response across the age-spectrum to define the age-dependent viral and host responses. Methods From March 2020-March 2022, we enrolled individuals across the age spectrum who presented to U.S. military medical treatment facilities with COVID-19-like symptoms. In this longitudinal cohort study, demographic and clinical data were collected in addition to nasopharyngeal swabs and peripheral blood. Magnitude of viral RNA was measured by quantitative PCR (qPCR) from nasopharyngeal samples and SARS-CoV-2-specific IgG antibodies were measured from blood with multiplex microsphere immunoassays. Results 4,768 SARS-CoV-2 positive participants were enrolled, among whom 42, 64, 89, 380, 948 and 245 individuals were in age brackets 0-4y, 5-11y, 12-17y, 18-44, 45-64y, and >65y, respectively. Viral load as measured by qPCR was determined to be similar across age groups within the first week post symptom onset. The magnitude of the IgG antibody response against the spike protein was also compared across age groups at early and convalescent time points and was higher in those over the age of 65 years. Conclusion Early viral load during acute infection did not correlate with age in individuals who experienced COVID-19. These findings diverge from other respiratory viruses, such as respiratory syncytial virus and influenza where children tend to have higher viral loads. In contrast, the magnitude of the antibody response against the spike protein correlated with older age at acute and convalescent time points. Together our data suggest that the host response against SAR-CoV-2 differs with age and is not associated with the acute viral load. Defining age-dependent immunity against SARS-CoV-2 has the potential to identify key immunologic responses that can be used to optimize treatment and vaccine strategies. Disclosures Julia S. Rozman, n/a, Astra Zeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Ryan C. Maves, MD, AiCuris: Grant/Research Support|Sound Pharmaceuticals: Grant/Research Support|Trauma Insights, LLC: Advisor/Consultant Mark P. Simons, PhD, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response David Tribble, MD, DrPH, Astra Zeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Timothy Burgess, MD, MPH, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Simon Pollett, MBBS, Astra Zeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response.

1955. Immunogenicity And Safety of a Virus-Like Particle (VLP) Protein Subunit SARS-CoV-2 Vaccine in Adults: a Phase 1/2 Study

Abstract Background COVID-19 continues to cause substantial morbidity and mortality globally. It is likely that booster vaccinations will be needed in future years to protect older adults and those with chronic medical conditions. We present interim topline results of a phase 1/2 study of IVX-411 [ACTRN12621000738820.; ACTRN12621000882820], an investigational VLP protein subunit SARS-CoV-2 vaccine, in adults aged 18–69 years (Figure 1). Methods In Part 1, 84 SARS-CoV-2-naïve adults were randomized to receive two doses on Days 0 and 28 of either IVX-411 (5, 25, or 125µg) ± adjuvant, or placebo (Figure 2a). In Part 2, 84 subjects received a single dose of either IVX-411 ± adjuvant or placebo 3–6 months after completion of a primary licensed vaccine regimen (Figure 2b). Solicited adverse events (AEs) were collected for 7 days after each dose, with immunogenicity assessed on Days 0, 28, and 49 [(Part 1) and on Days 0, 7 and 28 (Part 2). Primary outcomes in both parts were solicited and unsolicited AEs, neutralizing antibody titers, and spike protein-specific IgG antibody titers. Results Demographics were similar in the IVX-411 groups vs placebo. In Part 1 and Part 2, local reactogenicity was mild-to-moderate, with higher rates of AEs with increasing doses and addition of adjuvant (Figure 3a). Rates of systemic AEs were similar to placebo across groups (Figure 3b). No vaccine-related severe or serious AEs were noted. IVX-411 was immunogenic in both primary and booster vaccination: in SARS-CoV-2-naïve subjects, a limited dose effect was seen, with significantly higher antibody titers in the groups receiving adjuvanted IVX-411 vaccine (p< 0.01; Figure 4a). The magnitude of antibody responses was similar to, or below, Human Convalescent Sera levels. In previously vaccinated subjects, IVX-411 boosted baseline antibody titers, with no conclusive dose or adjuvant effect (Figure 4b). Immunogenicity was observed across all variants of concern (beta, delta, and omicron) in both parts, with up to 7- fold rises from baseline (Figure 5). Conclusion The study met all primary safety and immunogenicity objectives, with acceptable tolerability profiles in primary and booster vaccination. A clear adjuvant effect was observed in SARS-CoV-2-naïve subjects. Disclosures All Authors: No reported disclosures.

Body fat percentage is independently and inversely associated with serum antibody responses to SARS-CoV-2 mRNA vaccines

Vaccination is widely considered the most effective preventative strategy to protect against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. An individual’s exercise habits, and physical fitness have been shown to impact the immune response following vaccination using traditional vaccine platforms, but their effects are not well characterized following administration of newer vaccination technology (mRNA vaccines). We investigated these effects on the magnitude of antibody responses following SARS-CoV-2 mRNA vaccination while accounting for known covariates (age, sex, time since vaccination, and the type of vaccine administered). Adults of varying fitness levels (18–65 years; N = 50) who had received either the Moderna or Pfizer SARS-CoV-2 mRNA vaccine between 2 weeks and 6 months prior, completed health history and physical activity questionnaires, had their blood drawn, body composition, cardiorespiratory fitness, and strength assessed. Multiple linear regressions assessed the effect of percent body fat, hand grip strength, cardiorespiratory fitness, and physical activity levels on the magnitude of receptor binding domain protein (RBD) and spike protein subunit 1 (S1) and 2 (S2) while accounting for known covariates. Body fat percentage was inversely associated with the magnitude of S1 (p = 0.006, β = − 366.56), RBD (p = 0.003, β = − 249.30), and S2 (p = 0.106, β = − 190.08) antibodies present in the serum following SARS-CoV-2 mRNA vaccination. Given the increasing number of infections, variants, and the known waning effects of vaccination, future mRNA vaccinations such as boosters are encouraged to sustain immunity; reducing excess body fat may improve the efficacy of these vaccinations.

Magnitude of Antibody Response and Risk Factors for Reduced Immunogenicity after Two Doses of an Inactivated Whole-Virion COVID-19 Vaccine (CoronaVac<sup>®</sup>)

Magnitude of Antibody Response and Risk Factors for Reduced Immunogenicity after Two Doses of an Inactivated Whole-Virion COVID-19 Vaccine (CoronaVac<sup>®</sup>)

Immune recall improves antibody durability and breadth to SARS-CoV-2 variants.

Key features of immune memory are greater and faster antigen-specific antibody responses to repeat infection. In the setting of immune-evading viral evolution, it is important to understand how far antibody memory recognition stretches across viral variants when memory cells are recalled to action by repeat invasions. It is also important to understand how immune recall influences longevity of secreted antibody responses. We analyzed SARS-CoV-2 variant recognition, dynamics of memory B cells and secreted antibody over time after infection, vaccination, and boosting. We find that a two-dose SARS-CoV-2 vaccination regimen given after natural infection generated greater longitudinal antibody stability and induced maximal antibody magnitudes with enhanced breadth across Beta, Gamma, Delta and Omicron variants. A homologous 3rd mRNA vaccine dose in COVID-naïve individuals conferred greater cross-variant evenness of neutralization potency with stability that was equal to the hybrid immunity conferred by infection plus vaccination. Within unvaccinated individuals who recovered from COVID, enhanced antibody stability over time was observed within a subgroup of individuals that recovered more quickly from COVID and harbored significantly more memory B cells cross-reactive to endemic coronaviruses early after infection. These cross-reactive clones map to the conserved S2 region of SARS-CoV-2 spike with higher somatic hypermutation levels and greater target affinity. We conclude that SARS-CoV-2 antigen challenge histories in humans influence not only the speed and magnitude of antibody responses, but also functional cross-variant antibody repertoire composition and longevity.

Combined CpG and MPL as vaccine adjuvants improve immunity and heterosubtypic protection against lethal viral challenge in single dose and prime/boost regimens

Abstract Current Influenza A virus (IAV) vaccines show poor efficacy, often 40–60%. A strategy to improve effectiveness of IAV vaccines is to include adjuvants to activate innate immunity. We examined the potential of combined pattern recognition receptor agonists CpG and MPL to increase IAV vaccine induced protection. When administered in a single, low dose intramuscular hemagglutinin (HA) protein vaccine, mice receiving MPL + CpG experienced less morbidity after homologous challenge compared to mice receiving single agonists. In experiments analyzing heterosubtypic protection, vaccines containing MPL delivered intramuscularly (i.m.) showed increased protection against weight loss while the addition of CpG enhanced antibody responses but not survival. To determine if MPL and CpG have combinatory effects at different sites, HA and NP were delivered with MPL i.m. while HA and NP were simultaneously delivered with CpG intranasally (i.n.). Data demonstrate that combination MPL i.m. + CpG i.n. abrogated morbidity, but did not improve survival compared to MPL + CpG i.m. Further, mice given MPL + CpG produced IgG antibodies that were cross-reactive to H1N1 virus, yet magnitude of antibody responses did not correlate with protective efficacy. Finally, comparison of MPL i.m. + CpG i.n. in a prime/boost regimen, followed by heterosubtypic challenge, showed that weight loss was significantly lowered in mice that received prime/boost vaccination compared to mice that received prime only. Higher antibody responses induced by a second dose of vaccine did not correlate with protective capacity, suggesting that antibody levels, while indicators of vaccine immunogenicity, do not directly correlate with ability to protect mice from severe disease. Supported by Trudeau Institute and Clarkson University.

Antibody response to herpes simplex virus-1 is increased in autoimmune encephalitis.

Antibody response to herpes simplex virus-1 is increased in autoimmune encephalitis.

Abstract P3-23-02: Immunogenicity of SARS-CoV-2 vaccines in patients with breast cancer receiving CDK 4/6 inhibitors

Abstract Background: CDK 4/6 inhibitors have transformed the landscape of breast oncology. A CDK 4/6 inhibitor in combination with endocrine therapy is recommended as 1st line therapy for patients with metastatic hormone receptor positive breast cancer. CDK 4/6 inhibitors have purported immunomodulatory effects and while effective, myelosuppression is a common adverse effect of CDK 4/6 inhibitor treatment of breast cancer. The impact of CDK 4/6 inhibitor therapy on immunogenicity of vaccines is not known. In this study, we evaluated the spike antibody response to SARS-CoV-2 vaccines among patients with breast cancer receiving endocrine therapy with or without CDK 4/6 inhibitors.Methods: In the Cancer COVID and Vaccine (CANVAX) study eligible patients included patients with breast cancer who had completed all scheduled doses of SARS-CoV-2 vaccines. Chart review was conducted to identify patients who had received endocrine therapy with or without CDK 4/6 inhibitor. We used validated assays to measure anti-SARS-CoV-2 total IgA/M/G spike antibodies and virus neutralization. We evaluated the magnitude of antibody response based on geometric mean concentrations (GMCs) as well as the % of patients with inadequate seroconversion (defined as levels <100 U/ml). Independent T-test based on log-transformed antibody values was utilized to compare the spike antibody levels and p value of ≤ 0.05 was considered statistically significant.Results: Between April 2021 and June 2021, 203 patients with breast cancer were enrolled. As of the cut-off date (2nd July 2021), results were available for 73 patients treated with endocrine therapy alone (N = 23), or with CDK 4/6 inhibitor-based therapy (N = 50). Most were females (98.6%), white (83.6%), and had metastatic breast cancer (68.5%). 49.3% had received BNT162b2 (Pfizer), 37% mRNA1273 (Moderna), and 13.7% Ad26.COV2.S (Johnson and Johnson/Janssen) vaccines. Overall, the mean spike antibody levels were similar between patients treated with endocrine therapy alone vs CDK 4/6 inhibitor-based therapy (GMC: 326 vs. 719 U/mL; p=0.704). Mean spike antibody levels were higher in patients with early breast cancer vs. metastatic breast cancer (GMC: 555 vs. 465 U/mL; p=0.031). However, patients who received Ad26.COV2.S had lower levels of mean spike antibody levels (GMC 47 U/ml), compared with patients treated with BNT162b2 (GMC 400 U/ml) or mRNA1273 (GMC 2203 U/mL; P<0.01 for both comparisons). Comparison of neutralization titers in 66 individuals supported the above results. 11 (15.1%) patients had low antibody titers (<100U/ml) of seroconversion and 3 received a booster vaccine, with 1 having available repeat titer results thus far demonstrating a significant improvement.Conclusions: The majority of patients receiving CDK 4/6 inhibitor have adequate antibody response to SARS-CoV-2 vaccines, particularly mRNA vaccines. However, a minority of patients may require booster vaccine to augment immunity. Monitoring spike antibody levels could be helpful to identify patients with inadequate seroconversion and guide mitigation strategies for patients with breast cancer. Citation Format: Elyssa Denault, Erika Nakajima, Vivek Naranbhai, Alejandro Balazs, Lindsey Mortensen, Elizabeth Niehoff, Caroline Barabell, Jennifer A. Hutchinson, Seth A. Wander, Aron S. Rosenstock, Leif W. Ellisen, Beverly Moy, Steven J. Isakoff, Justin F. Gainor, A. John Iafrate, Aditya Bardia, Laura M. Spring. Immunogenicity of SARS-CoV-2 vaccines in patients with breast cancer receiving CDK 4/6 inhibitors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-23-02.

Different adjuvanted pediatric HIV envelope vaccines induced distinct plasma antibody responses despite similar B cell receptor repertoires in infant rhesus macaques.

Different HIV vaccine regimens elicit distinct plasma antibody responses in both human and nonhuman primate models. Previous studies in human and non-human primate infants showed that adjuvants influenced the quality of plasma antibody responses induced by pediatric HIV envelope vaccine regimens. We recently reported that use of the 3M052-SE adjuvant and longer intervals between vaccinations are associated with higher magnitude of antibody responses in infant rhesus macaques. However, the impact of different adjuvants in HIV vaccine regimens on the developing infant B cell receptor (BCR) repertoire has not been studied. This study evaluated whether pediatric HIV envelope vaccine regimens with different adjuvants induced distinct antigen-specific memory B cell repertoires and whether specific immunoglobulin (Ig) immunogenetic characteristics are associated with higher magnitude of plasma antibody responses in vaccinated infant rhesus macaques. We utilized archived preclinical pediatric HIV vaccine studies PBMCs and tissue samples from 19 infant rhesus macaques immunized either with (i) HIV Env protein with a squalene adjuvant, (ii) MVA-HIV and Env protein co-administered using a 3-week interval, (iii) MVA-HIV prime/ protein boost with an extended 6-week interval between immunizations, or (iv) with HIV Env administered with 3M-052-SE adjuvant. Frequencies of vaccine-elicited HIV Env-specific memory B cells from PBMCs and tissues were similar across vaccination groups (frequency range of 0.06-1.72%). There was no association between vaccine-elicited antigen-specific memory B cell frequencies and plasma antibody titer or avidity. Moreover, the epitope specificity and Ig immunogenetic features of vaccine-elicited monoclonal antibodies did not differ between the different vaccine regimens. These data suggest that pediatric HIV envelope vaccine candidates with different adjuvants that previously induced higher magnitude and quality of plasma antibody responses in infant rhesus macaques were not driven by distinct antigen-specific memory BCR repertoires.

Humoral Response to Microbial Biomarkers in Rheumatoid Arthritis Patients.

Background/Objective: Chronic humoral immune response against multiple microbial antigens may play a crucial role in the etiopathogenesis of rheumatoid arthritis (RA). We aimed to assess the prevalence and magnitude of antibody response against various bacterial and viral immunogen peptides in the sera of RA patients compared with the general population. Methods: Polyclonal IgG antibodies (Abs) specific for peptides derived from Porphyromonas gingivalis (RgpA, Kpg), Aggregatibacter actinomycetemcomitans (LtxA1, LtxA2), Mycobacterium avium subsp. paratuberculosis (MAP4027), Epstein–Barr virus (EBNA1, EBVBOLF), and human endogenous retrovirus (HERV-W env-su) were detected by ELISA in serum samples from 148 consecutive RA patients and 148 sex and age-matched healthy controls (HCs). In addition, the presence of a relationship between the positivity and the titer of antibodies and RA descriptors was explored by bivariate correlation analysis. Results: RA patients exhibit a higher prevalence of humoral immune response against all tested peptides compared to HCs with a statically significant difference for MAP4027 (30.4% vs. 10.1%), BOLF (25.7% vs. 8.1%), RgpA (24.3% vs. 9.4%), HERV W-env (20.3% vs. 9.4%), and EBNA1 (18.9% vs. 9.4%) peptides. Fifty-three (35.8%) out of 148 RA serum and 93 (62.8%) out of 148 HCs were negative for all pathogen-derived peptides. There was a significant correlation between OD values obtained by ELISA test against all peptides (p < 0.0001). We also found an increased titer and prevalence of Abs against LtxA1 and LtxA2 in seropositive vs. seronegative RF (p = 0.019, p = 0.018). Conclusion: This study demonstrates a significantly increased humoral response against multiple pathogens in patients with RA and implies that they could be an important factor in the pathogenesis of the disease. Therefore, the role of each individual pathogen in RA needs to be further investigated.

Antibody Responses After mRNA-Based COVID-19 Vaccination in Residential Older Adults: Implications for Reopening

ObjectiveCOVID-19 disproportionately impacts residents in long-term care facilities. Our objective was to quantify the presence and magnitude of antibody response in vaccinated, older adult residents at assisted living, personal care, and independent living communities.DesignA cross-sectional quality improvement study was conducted March 15 – April 1, 2021 in the greater Pittsburgh region.Setting and PopulationParticipants were older adult residents at assisted living, personal care, and independent living communities, who received mRNA-based COVID-19 vaccine. Conditions that impair immune responses were exclusionary criteria.MethodsSera were collected to measure IgG anti-SARS-CoV-2 antibody level with reflex to total anti-SARS-CoV-2 immunoglobulin levels, and blinded evaluation of SARS-CoV-2 pseudovirus neutralization titers. Descriptive statistics, Pearson correlation coefficients, and multiple linear regression analysis evaluated relationships between factors potentially associated with antibody levels. Spearman correlations were calculated between antibody levels and neutralization titers.ResultsAll participants (N = 70) had received two rounds of vaccination and were found to have antibodies with wide variation in relative levels. Antibody levels trended lower in males, advanced age, current use of steroids, and longer length of time from vaccination. Pseudovirus neutralization titer levels were strongly correlated (P < .001) with Beckman Coulter antibody levels [D614 G NT50, rs = 0.91; B.1.1.7 (UK) NT50, rs = 0.91].Conclusions and ImplicationsHigher functioning, healthier, residential older adults mounted detectable antibody responses when vaccinated with mRNA-based COVID-19 vaccines. Data suggests some degree of immunity is present during the immediate period following vaccination. However, protective effects remain to be determined in larger studies as clinical protection is afforded by ongoing adaptive immunity, which is known to be decreased in older adults. This study provides important preliminary results on level of population risk in older adult residents at assisted living, personal care, and independent living communities to inform reopening strategies, but are not likely to be translatable for residents in nursing homes.

Recombinant HA-based vaccine outperforms split and subunit vaccines in elicitation of influenza-specific CD4 T cells and CD4 T cell-dependent antibody responses in humans

Although traditional egg-based inactivated influenza vaccines can protect against infection, there have been significant efforts to develop improved formats to overcome disadvantages of this platform. Here, we have assessed human CD4 T cell responses to a traditional egg-based influenza vaccine with recently available cell-derived vaccines and recombinant baculovirus-derived vaccines. Adults were administered either egg-derived Fluzone®, mammalian cell-derived Flucelvax® or recombinant HA (Flublok®). CD4 T cell responses to each HA protein were assessed by cytokine EliSpot and intracellular staining assays. The specificity and magnitude of antibody responses were quantified by ELISA and HAI assays. By all criteria, Flublok vaccine exhibited superior performance in eliciting both CD4 T cell responses and HA-specific antibody responses, whether measured by mean response magnitude or percent of responders. Although the mechanism(s) underlying this advantage is not yet clear, it is likely that both qualitative and quantitative features of the vaccines impact the response.

In silico design of a universal carrier protein: A potential solution to the variable immunogenicity observed in past vaccines against drugs of abuse

Abstract Vaccines against drugs of abuse (VADAs) show promise as a possible therapeutic for the alleviation of addiction due to their ability to modulate intake behavior via the altering of drug pharmacokinetics. In the past, however, these vaccines have failed to show clinical efficacy due to extensive variability in the magnitude of antibody response between individual vaccinees. Correspondingly, the future success of VADAs hinges directly on whether or not researchers can find ways to engineer more broadly effective vaccines. Differences in response must, to some extent, be the result of variable capacities for each individual’s immune system to process and/or present antigens. As such, we speculate that future VADAs will need to target the three key stages of vaccine processing, recognition, processing, and presentation, in order to achieve clinical effectiveness. Here, we describe a project aiming to engineer a broadly effective carrier protein based on this concept. Using haplotype frequency data provided by Be the Match, HLA-DQ and -DR haplotypes covering 99% of the population were selected for analysis. Next, the most common carrier proteins used in conjugate vaccine formulations were analyzed for MHC II epitope content using these haplotypes and NetMHCIIPan 3.2 prediction software. Finally, a modified version of the prediction output was used to excise the most likely MHC II epitopes. The highest-ranked epitopes were then stitched together using linkers designed with chemical conjugation sites and cathepsin cleavage sequences and subsequently tethered to cholera toxin subunit B. These results present the successful design of an in silico derived, broadly effective carrier protein to be used in future VADA formulations.

Ducks induce rapid and robust antibody responses than chickens at early time after intravenous infection with H9N2 avian influenza virus

BackgroundCompared with chickens, ducks are normally resistant to avian influenza virus without clinical signs while they habor almost all subtypes of influenza A viruses. To date, however the mechanism for duck anti-influenza has not been completely understood. The H9N2 avian influenza virus (AIV) is the most prevalent subtype of influenza A virus that infects chickens and ducks in China. However, H9N2 AIV replication and the host immune response in these domestic birds has not been systematically investigated.MethodsIn the present study, we compared the kinetics and magnitudes of antibody responses in chickens and ducks after infection with H9N2 AIV by the intranasal route or intravenous route. Furthermore, we determined the viral replication and distribution in chickens and ducks after infection with H9N2 AIV by the intravenous route.ResultsOur results revealed that the antibody response was rapid and robust in ducks than in chickens at early time (2-3dpi) after intravenous infection with H9N2 AIVs, while delayed and lower antibody detected in ducks than in chickens after intranasal infection with H9N2 AIVs. The virus was detected in multiple organs tissues in chickens but not in ducks infected by the intravenous route.ConclusionsOur results provide the evidence that humoral immune response could play a critical role in duck resistance for influenza, which expands our knowledge on duck anti-influenza characteristics.

Cross-reactive antibody-dependent cellular cytotoxicity antibodies are increased by recent infection in a household study of influenza transmission.

ObjectivesInfluenza causes a spectrum of disease from asymptomatic infection to fatal outcome, and pre‐existing immunity can alter susceptibility and disease severity. In a household transmission study, we recruited outpatients with confirmed influenza virus infection and prospectively identified secondary infections in their household contacts, therefore identifying infection cases with baseline samples for determining immune‐mediated protection from influenza infection.MethodsWe examined baseline broadly reactive immune correlates of relevance to universal vaccine development, specifically antibody‐dependent cytotoxic (ADCC) antibodies and T‐cell responses in functional assays. Antibodies were assessed in a cell‐based NK cell degranulation assay by flow cytometry, and T‐cell responses were assessed by IFN‐γ intracellular cytokine staining flow cytometry assay.ResultsThe magnitude of antibody responses and ADCC function for multiple influenza‐specific proteins was lower in participants who became infected, consolidating the role of pre‐existing antibodies in protection from seasonal influenza virus infection. Among H1N1‐infected contacts, we found that higher levels of pre‐existing H1‐haemagglutinin ADCC responses correlated with reduced symptom severity. Recent infection boosted the titre and magnitude of haemagglutinin‐, neuraminidase‐ and nucleoprotein‐specific ADCC antibodies. Limited T‐cell samples precluded conclusions on the role of pre‐existing T‐cell responses.ConclusionsOverall, ADCC responses are a protective correlate against influenza virus infection that should be considered in future vaccine development and evaluation.Influenza‐specific ADCC responses are elevated in uninfected subjects, associated with reduced symptoms and boosted by recent infection, whilst HA stem and NA IgG are also elevated in uninfected participants irrespective of ADCC function.

Liposome-Encapsulated Human Immunodeficiency Virus-1 gp120 Induces Potent V1V2-Specific Antibodies in Humans.

In the RV144 trial, human immunodeficiency virus (HIV)-1 gp120 V1V2 antibodies correlated inversely with risk of HIV-1 infection; however, the titers waned quickly. We hypothesized that a more potent adjuvant might enhance the magnitude and durability of V1V2 antibodies. We examined archived sera from a phase I randomized, double-blind placebo-controlled trial, conducted in HIV-1-uninfected individuals, vaccinated with HIV-1SF-2 rgp120 either adsorbed to aluminum hydroxide (aluminum hydroxide arm) or encapsulated in liposomes containing monophosphoryl lipid A (MPL®) and then adsorbed to aluminum hydroxide (liposomal arm). The median immunoglobulin G antibody titers across weeks 10-112 were higher in the liposomal arm against subtypes B (2- to 16-fold), AE (4- to 8-fold), and C (4- to 16-fold) V1V2 proteins. High titers were maintained even at 10 months after last boost in the liposomal compared with the aluminum hydroxide arm. The antibodies exhibited antibody-dependent cellular cytotoxicity (ADCC) and α4β7-integrin receptor inhibition-binding functions. Inclusion of 2 adjuvants in the vaccine formulation, aluminum hydroxide, and liposomal MPL®, induced robust, durable, and functional antibodies. Based on the magnitude of antibody responses and the percentage of coiled and β-sheet in the predicted V2/V3-peptide structure, we speculate that liposomal gp120 was presented in a conformation that favored the induction of robust antibody responses.

For flu vaccines, age matters

Infectious Disease Development of a broad flu vaccine has been hampered by a lack of insight into protective mechanisms of seasonal vaccines across individuals. Avey et al. performed a systems-level analysis on multiple influenza vaccination cohorts spanning distinct geographical locations and vaccination seasons. They identified prevaccination predictive transcriptional signatures of influenza vaccination responses. They then validated nine genes and three gene cohorts that were associated with the magnitude of antibody response in an independent cohort. However, these signatures were specific to young patients and had an inverse correlation in older individuals. These data may help to predict antibody response to influenza vaccination and shed light on the distinct mechanisms governing immune responses in young and old people. Sci. Immunol. 2 , eaal4656 (2017).

Antigen spread (AgS) after sipuleucel-T (sip-T): A cross-trial comparison of 4 sip-T clinical trials of patients (pts) with prostate cancer (PC).

143 Background: Sip-T, an FDA-approved autologous immunotherapy for pts with asymptomatic or minimally symptomatic metastatic castration-resistant PC (mCRPC), is manufactured from peripheral blood mononuclear cells cultured with PA2024, a fusion antigen of prostatic acid phosphatase (PAP) conjugated to granulocyte macrophage colony-stimulating factor. In sip-T–treated pts, antibody responses to PA2024/PAP (target antigens) and AgS (antibody responses to secondary [2°] antigens) correlate with improved OS (Sheikh 2013; GuhaThakurta 2015). We assessed if a greater magnitude of AgS would be observed in an earlier PC disease stage when the immune system is more intact. Methods: Pt serum was from 1 non-metastatic, androgen-dependent PC (ADPC) sip-T trial (STAND, sip-T + androgen deprivation, NCT01431391) and 3 mCRPC sip-T trials (IMPACT, sip-T vs control, NCT00065442; STAMP, sip-T + abiraterone acetate, NCT01487863; STRIDE, sip-T + enzalutamide, NCT01981122). Using a Luminex assay, mean fold-change in IgG responses to target and 2° cancer-related antigens (PSA, LGALS3, LGALS8, ERAS, KRAS, KLK2) was evaluated from baseline to wk 6. Results: AgS was evaluated in 308 pts. The mean fold-change in IgG responses to target antigens was greater for ADPC vs mCRPC pts (p &lt; 0.01). Moreover, the magnitude of IgG responses was greater for most 2° antigens in ADPC vs mCRPC pts (p &lt; 0.05; Table), except for PSA and KLK2 in ADPC vs STRIDE pts. Conclusions: The magnitude ofantibody responses to target and 2° antigens was greater earlier in the PC disease course, consistent with increased antigen-presenting cell activation in ADPC vs mCRPC pts. Increased AgS likely reflects stronger sip-T–induced immune responses, previously associated with extended OS in mCRPC (Sheikh 2013; GuhaThakurta 2015). Future research is warranted on the clinical benefit of sip-T earlier in the PC disease course and the potential impact of androgen suppression on the magnitude of AgS and outcomes. Clinical trial information: NCT01431391; NCT00065442; NCT01487863; NCT01981122. [Table: see text]