ImmunoPET imaging of hematological malignancies: From preclinical promise to clinical reality

Immuno-positron emission tomography (immunoPET) imaging is a paradigm-shifting imaging technique for whole-body and all-lesion tumor detection, based on the combined specificity of tumor-targeting vectors [e.g., monoclonal antibodies (mAbs), nanobodies, and bispecific antibodies] and the sensitivity of PET imaging. By noninvasively, comprehensively, and serially revealing heterogeneous tumor antigen expression, immunoPET imaging is gradually improving the theranostic prospects for hematological malignancies. In this review, we summarize the available literature regarding immunoPET in imaging hematological malignancies. We also highlight the pros and cons of current conjugation strategies, and modular chemistry that can be leveraged to develop novel immunoPET probes for hematological malignancies. Lastly, we discuss the use of immunoPET imaging in guiding antibody drug development.     

Effect of recent seasonal influenza vaccination on serum antibody responses to candidate pandemic influenza A/H5N1 vaccines: A meta-analysis

Recent studies have suggested that among those receiving seasonal influenza vaccine (SIV), reduced immunogenicity is observed in recently vaccinated (RV; within the past season or 2) persons when compared with those not recently vaccinated (NRV). We performed a meta-analysis to assess the effect of recent immunization with SIV on serum H5 hemagglutination inhibition (HAI) antibody responses after influenza A/H5N1 vaccination using data from a series of randomized controlled trials. The primary outcome was seroconversion measured by HAI assays following receipt of 2 doses of H5N1 vaccine. The geometric mean titer (GMT) of serum HAI antibody after vaccination was the secondary outcome. Analyses were performed using propensity score (PS) matching. The PS for each individual in the meta-analysis cohort was calculated using logistic regression and covariates included age, gender, race, antigen dose, adjuvant, statin use and vaccine manufacturer. 2015 subjects enrolled in 7 clinical trials were eligible for inclusion in the meta-analysis cohort; among these, 915 (45%) were RV. 901 RV subjects were matched (1:1) with replacement to a subject who was NRV. Subjects who received SIV within the previous season were significantly less likely to seroconvert following H5N1 vaccination (adjusted odds ratio 0.76; 95%CI 0.60–0.96; p = 0.024), and the GMT was 18% higher among NRV subjects (GM ratio of HAI antibody 1.18; 95%CI 1.04–1.33; p = 0.008). Further work is needed to better define the effects of, and mechanisms contributing to, reduced immune responses to H5N1 vaccine among RV subjects.     

Single-dose combination nanovaccine induces both rapid and durable humoral immunity and toxin neutralizing antibody responses against Bacillus anthracis

Bacillus anthracis, the causative agent of anthrax, continues to be a prominent biological warfare and bioterrorism threat. Vaccination is likely to remain the most effective and user-friendly public health measure to counter this threat in the foreseeable future. The commercially available AVA BioThrax vaccine has a number of shortcomings where improvement would lead to a more practical and effective vaccine for use in the case of an exposure event. Identification of more effective adjuvants and novel delivery platforms is necessary to improve not only the effectiveness of the anthrax vaccine, but also enhance its shelf stability and ease-of-use. Polyanhydride particles have proven to be an effective platform at adjuvanting the vaccine-associated adaptive immune response as well as enhancing stability of encapsulated antigens. Another class of adjuvants, the STING pathway-targeting cyclic dinucleotides, have proven to be uniquely effective at inducing a beneficial inflammatory response that leads to the rapid induction of high titer antibodies post-vaccination capable of providing protection against bacterial pathogens. In this work, we evaluate the individual contributions of cyclic di-GMP (CDG), polyanhydride nanoparticles, and a combination thereof towards inducing neutralizing antibody (nAb) against the secreted protective antigen (PA) from B. anthracis. Our results show that the combination nanovaccine elicited rapid, high titer, and neutralizing IgG anti-PA antibody following single dose immunization that persisted for at least 108 DPI.     

Impact of prior vaccination on antibody response and influenza-like illness among Australian healthcare workers after influenza vaccination in 2016

BackgroundEpidemiological studies suggest that influenza vaccine effectiveness decreases with repeated administration. We examined antibody responses to influenza vaccination among healthcare workers (HCWs) by prior vaccination history and determined the incidence of influenza infection.MethodsHCWs were vaccinated with the 2016 Southern Hemisphere quadrivalent influenza vaccine. Serum samples were collected pre-vaccination, 21–28 days and 7 months post-vaccination. Influenza antibody titres were measured at each time-point using the haemagglutination inhibition (HI) assay. Immunogenicity was compared by prior vaccination history.ResultsA total of 157 HCWs completed the study. The majority were frequently vaccinated, with only 5 reporting no prior vaccinations since 2011. Rises in titres for all vaccine strains among vaccine-naïve HCWs were significantly greater than rises observed for HCWs who received between 1 and 5 prior vaccinations (p < 0.001, respectively). Post-vaccination GMTs against influenza A but not B strains decreased as the number of prior vaccinations increased from 1 to 5. There was a significant decline in GMTs post-season for both B lineages. Sixty five (41%) HCWs reported at least one influenza-like illness episode, with 6 (4%) identified as influenza positive.ConclusionsVarying serological responses to influenza vaccination were observed among HCWs by prior vaccination history, with vaccine-naïve HCWs demonstrating greater post-vaccination responses against A(H3N2).     

Interstitial lung diseases in children

Interstitial lung disease (ILD) in children (chILD) is a heterogeneous group of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. The pathogenesis of the various chILD is complex and the diseases share common features of inflammatory and fibrotic changes of the lung parenchyma that impair gas exchanges. The etiologies of chILD are numerous. In this review, we chose to classify them as ILD related to exposure/environment insults, ILD related to systemic and immunological diseases, ILD related to primary lung parenchyma dysfunctions and ILD specific to infancy. A growing part of the etiologic spectrum of chILD is being attributed to molecular defects. Currently, the main genetic mutations associated with chILD are identified in the surfactant genes SFTPA1, SFTPA2, SFTPB, SFTPC, ABCA3 and NKX2-1. Other genetic contributors include mutations in MARS, CSF2RA and CSF2RB in pulmonary alveolar proteinosis, and mutations in TMEM173 and COPA in specific auto-inflammatory forms of chILD. However, only few genotype-phenotype correlations could be identified so far. Herein, information is provided about the clinical presentation and the diagnosis approach of chILD. Despite improvements in patient management, the therapeutic strategies are still relying mostly on corticosteroids although specific therapies are emerging. Larger longitudinal cohorts of patients are being gathered through ongoing international collaborations to improve disease knowledge and targeted therapies. Thus, it is expected that children with ILD will be able to reach the adulthood transition in a better condition.     

Endpoint and epitope-specific antibody responses as correlates of vaccine-mediated protection of mice against ricin toxin

The successful licensure of vaccines for biodefense is contingent upon the availability of well-established correlates of protection (CoP) in at least two animal species that can be applied to humans, without the need to assess efficacy in the clinic. In this report we describe a multivariate model that combines pre-challenge serum antibody endpoint titers (EPT) and values derived from an epitope profiling immune-competition capture (EPICC) assay as a predictor in mice of vaccine-mediated immunity against ricin toxin (RT), a Category B biothreat. EPICC is a modified competition ELISA in which serum samples from vaccinated mice were assessed for their ability to inhibit the capture of soluble, biotinylated (b)-RT by a panel of immobilized monoclonal antibodies (mAbs) directed against four immunodominant toxin-neutralizing regions on the enzymatic A chain (RTA) of RT. In a test cohort of mice (n = 40) vaccinated with suboptimal doses of the RTA subunit vaccine, RiVax®, we identified two mAbs, PB10 and SyH7, which had EPICC inhibition values in pre-challenge serum samples that correlated with survival following a challenge with 5 × LD₅₀ of RT administered by intraperitoneal (IP) injection. Analysis of a larger cohort of mice (n = 645) revealed that a multivariate model combining endpoint titers and EPICC values for PB10 and SyH7 as predictive variables had significantly higher statistical power than any one of the independent variables alone. Establishing the correlates of vaccine-mediated protection in mice represents an important steppingstone in the development of RiVax® as a medical countermeasure under the United States Food and Drug Administration’s “Animal Rule.”