A Population-Based Threshold of Protection for COVID-19 Vaccines

Correlates of protection for COVID-19 vaccines are urgently needed to license and deploy additional vaccines. We measured immune responses to four COVID-19 vaccines of proven efficacy using a single serological platform calibrated to the international standard. IgG anti-Spike antibodies correlated significantly with efficacies for original virus and alpha variant and were highly correlated with ID50 neutralization in a validated pseudoviral assay. The protective threshold for each vaccine was calculated for IgG anti-Spike antibody. The mean protective threshold for all vaccine studies was 154 BAU/ml (95%CI 42-559), and for the vaccine studies with antibody distributions that enabled precise estimation of thresholds (i.e. leaving out 2-dose mRNA studies) was 60 BAU/ml (95%CI 35-102). We propose that the proportion of individuals with responses above the appropriate protective threshold together with the geometric mean concentration can be used in comparative non-inferiority studies with licensed vaccines to ensure that new vaccines will be efficacious.

Alpha-1 antitrypsin deficiency: clarifying the role of the putative protective threshold

AATD is the only readily identifiable monogenic cause of COPD. To date the only condition-specific treatment for AATD-associated COPD is weekly administration of intravenous purified pooled human AAT (IV-AAT). Uncertainties regarding which AATD genotypes should benefit from IV-AAT persist. IV-AAT is costly and involves weekly administration of a plasma product. Much of the risk stratification has been centred around the long-accepted hypothesis of a “putative protective threshold” of 11 µM (0.57 g·L−1) in serum. This hypothesis has become central to the paradigm of AATD care, though its derivation and accuracy for defining risk of disease remain unclear.We review the literature and examine the association between the 11 µM threshold and clinical outcomes to provide context and insight into the issues surrounding this topic.We found no data which demonstrates an increased risk of COPD dependent on the 11 µM threshold. Moreover, an abundance of recent clinical data examining this threshold refutes the hypothesis. Conversely, the use of 11 µM as a treatment target in appropriate ZZ individuals is supported by clinical evidence, although more refined dosing regimens are being explored.Continued use of the 11 µM threshold as a determinant of clinical risk is questionable, perpetuates inappropriate AAT-augmentation practices, may drive increased healthcare expenditure and should not be used as an indicator for commencing treatment.Genotype represents a more proven indicator of risk, with ZZ and rare ZZ-equivalent genotypes independently associated with COPD. New and better risk assessment models are needed to provide individuals diagnosed with AATD with reliable risk estimation and optimised treatment goals.

Gender Differences in the Level of Antibodies to Measles Virus in Adults

Individuals without a protective antibody level are susceptible to measles infection. There are differences in the persistence of antibodies after vaccination and infection, while the impact of gender on this process has not been sufficiently studied. Measles Ig G antibodies were measured in 1742 employees of a large hospital facility—403 men and 1339 women aged from 25 to 67 years; 15% participants had antibody levels less than the protective threshold of ≥0.18 IU/mL. Significant differences were found in the age group 40–49, where the level of IgG antibodies to measles among men was higher than among women (1.51 IU/mL (0.41; 3.38) vs. 0.70 IU/mL (0.22;1.98) respectively, (U = 3.2, p = 0,001)); in the age group 60 and older, by contrast, the level of antibodies among women was higher compared to men (3.29 IU/mL (1.72; 4.07) vs. 2.90 IU/mL (1.46; 3.53) respectively (U = 2.2, p = 0.03)). The proportion of seronegative women in the age group 40–49 was significantly higher than of seronegative men: 22 [18–26]% and 11 [6–18]% respectively (χ2 = 7.0, p = 0.001). The revealed gender characteristics that affect persistence of measles immunity may be important in personalization of vaccinal prevention for men and women.

Diphtheria Immunity in Australia: Should we be Concerned?

Objective: We report the results of the 2007 national serological survey of immunity to diphtheria in Australia to assess the impact of recent schedule changes on diphtheria immunity, and the adequacy of current policy in the context of increased international travel of people and pathogens. Methods: Residual sera (n =1656) collected opportunistically from Australian laboratories in 2007 were tested for diphtheria antibody levels using an enzyme immunoassay, with the protective threshold defined as ≥0.1 IU/mL. About 40% of adults aged ≥30 years are susceptible to diphtheria; following the removal of the 18-month booster and its replacement with a dose in adolescence offered through school-based dTpa vaccination program, 59% of children aged 3 years were susceptible to diphtheria, whilst adolescents demonstrated improved immunity. Results: There is no apparent boosting of diphtheria immunity from meningococcal group C conjugate (MCC) or seven-valent pneumococcal conjugate (7vPCV) vaccines in relevant age groups. Conclusion: Australians who travel to diphtheria-endemic areas should be up-to-date with their vaccinations. Close monitoring of population immunity levels against diphtheria remains important to ensure that immunity does not decline to a level where wide-spread transmission would be possible.V

Clinical considerations in individuals with α1-antitrypsin PI*SZ genotype

α1-Antitrypsin deficiency (AATD), characterised by reduced levels or functionality of α1-antitrypsin (AAT), is a significantly underdiagnosed genetic condition that predisposes individuals to lung and liver disease. Most of the available data on AATD are based on the most common, severe deficiency genotype (PI*ZZ); therefore, treatment and monitoring requirements for individuals with the PI*SZ genotype, which is associated with a less severe AATD, are not as clear. Recent genetic data suggest the PI*SZ genotype may be significantly more prevalent than currently thought, due in part to less frequent identification in the clinic and less frequent reporting in registries. Intravenous AAT therapy, the only specific treatment for patients with AATD, has been shown to slow disease progression in PI*ZZ individuals; however, there is no specific evidence for AAT therapy in PI*SZ individuals, and it remains unclear whether AAT therapy should be considered in these patients. This narrative review evaluates the available data on the PI*SZ genotype, including genetic prevalence, the age of diagnosis and development of respiratory symptoms compared with PI*ZZ individuals, and the impact of factors such as index versus non-index identification and smoking history. In addition, the relevance of the putative 11 µM “protective threshold” for AAT therapy and the risk of liver disease in PI*SZ individuals is explored. The purpose of this review is to identify open research questions in this area, with the aim of optimising the future identification and management of PI*SZ individuals.

Streptococcus pneumoniae Nasopharyngeal Carriage among PCV-10-Vaccinated HIV-1-Infected Children with Maintained Serological Memory in Ethiopia

Streptococcus pneumoniae (S. pneumoniae) vaccines have substantially reduced the burden of invasive pneumococcal diseases (IPDs) worldwide. Despite high coverage with S. pneumoniae vaccination, upper-respiratory-tract colonization by S. pneumoniae is still common. We assessed maintenance of serological responses to S. pneumoniae serotypes included in PCV-10 by ELISA in HIV-1-infected children (n = 50) and age-matched controls (n = 50) in Ethiopia. We isolated S. pneumoniae in nasopharyngeal swabs and determined S. pneumoniae serotype by whole genome sequencing (WGS). Comparable levels of S. pneumoniae serotype-specific IgG concentrations were detected in plasma of HIV-1-infected children and matched controls, with geometric mean concentrations (GMCs) consistently higher than the protective threshold for PCV-10 serotypes of 0.35 μg/mL. We isolated S. pneumoniae from 38 (out of 97) nasopharyngeal swabs, 25 from HIV-1-infected children and 13 from controls. WGS based serotyping revealed 22 known S. pneumoniae serotypes and 2 nontypeable (NT) isolates. Non-PCV-10 serotypes represented >90% of isolates. We showed that HIV-1-infected children and matched controls in Ethiopia carry a level of maintained serological memory to PCV-10 considered protective for IPDs. We identified a higher proportion of nasopharyngeal carriage with highly pathogenic S. pneumoniae non-PCV strains among HIV-1-infected children compared to controls.

Mass balance and long-term soil accumulation of trace elements in arable crop systems amended with urban composts or cattle manure during 17 years

Organic waste products (OWP) application to crop lands makes possible nutrients recycling. However, it can result in long-term accumulation of trace elements (TE) in soils. The present study aimed at (i) assessing the impact of regular applications of urban composts and manure on the TE contents of topsoils and crops in a long-term field experiment, (ii) comparing the TE mass balances with the stock variations of TE in soils, and (iii) proposing a prospective evaluation of this practice, based on estimated soil safe threshold values and simulations of soil TE accumulation for 100 years. In the long-term field experiment, physico-chemical properties and TE contents (Cd, Cr, Cu, Hg, Ni, Pb and Zn) have been measured in OWP, soils, plants and leaching waters for the period 1998–2015, and used for mass balance calculations and long-term simulations of TE accumulations. The composts of green wastes and sludge (GWS) and of municipal solid waste (MSW) were the OWP with the largest TE contents, while the farmyard manure tended to have the lowest. Repeated application of OWP led to significant accumulation of Zn and Cu in the topsoil layer (not for Cr, Cd, Hg, Ni, Pb), especially with GWS, without overpassing calculated protective threshold values. No effect of repeated application of OWP has been observed on TE contents in grains (wheat, maize, barley). The positive mass balance has been dominated by the input flux of TE through OWP and resulted in the observed increases of soil stocks for Cu and Zn. Prospective simulation of soil content evolution until 2100 showed that soil content reached 0.4 mg Cd kg−1 soil (GWS, MSW), 38 mg Cu kg−1 soil (GWS) and 109 mg Zn kg−1 soil (GWS), which remained lower than protective threshold values.

Evaluation of a Validated Luminex-Based Multiplex Immunoassay for Measuring Immunoglobulin G Antibodies in Serum to Pneumococcal Capsular Polysaccharides

ABSTRACT This article describes the results of a study designed to bridge the World Health Organization (WHO) pneumococcal enzyme-linked immunosorbent assay (ELISA) platform to the validated Luminex-based 13-plex direct immunoassay (dLIA) platform developed by Pfizer, Inc. Both assay platforms quantify serotype-specific serum IgG antibodies (in micrograms per milliliter) against an international reference standard serum. The primary goal of this study was to determine if the dLIA is a suitable replacement for the ELISA to support clinical vaccine studies that include the evaluation of immune responses to serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. Serum samples were selected from four pivotal 13-valent pneumococcal conjugate vaccine (13vPnC; Prevnar 13) clinical trials on the basis of their serotype-specific IgG concentrations by ELISA. In these studies, subjects were immunized either with 13vPnC or with 7-valent pneumococcal conjugate vaccine (7vPnC; Prevnar). There were 1,528 of 1,574 selected samples with sufficient remaining volume for reanalysis in the dLIA. A comparison of assay results from the dLIA and ELISA platforms showed clear and robust linear quantitative relationships across all 13 serotypes. In addition, lower IgG antibody concentrations in preimmunization samples were measured in the dLIA, thus allowing better differentiation between preimmunization and low-titer postimmunization samples. Overall, the results showed that the established population-level protective threshold IgG concentration, 0.35 µg/ml of serotype-specific serum IgG antibodies, is appropriate for use for data generated using the dLIA platform developed by Pfizer, Inc., for 10 serotypes: serotypes 1, 3, 4, 6A, 7F, 9V, 14, 18C, 19F, and 23F. On the basis of the extensive bridging analyses, however, the use of dLIA cutoff values of 0.23, 0.10, and 0.12 µg/ml is recommended for serotypes 5, 6B, and 19A, respectively. This adjustment will ensure that the consistency of the established population-level protective threshold IgG concentration is maintained when switching from the ELISA to the dLIA platform. The results of this bridging study demonstrate that the 13-plex dLIA platform is a suitable replacement for the WHO reference ELISA platform. IMPORTANCE The pneumococcal enzyme-linked immunosorbent assay (ELISA) measures IgG antibodies in human serum, and it is an important assay that supports licensure of pneumococcal vaccines. The immune correlate of protection, 0.35 µg/ml of IgG antibodies, was determined by the ELISA method. Pfizer has developed a new Luminex-based assay platform to replace the ELISA. These papers describe the important work of (i) validating the Luminex-based assay and (ii) bridging the immune correlate of protection (0.35 µg/ml IgG) to equivalent values reported by the Luminex platform.