Introducing new recombinant protein antigens to existing pediatric combination vaccines is important in improving coverage and affordability, especially in low- and middle-income countries (LMICs). This case-study highlights the analytical and formulation challenges encountered with three recombinant non-replicating rotavirus vaccine (NRRV) antigens (t-NRRV formulated with Alhydrogel® adjuvant, AH) combined with a mock multidose formulation of a pediatric pentavalent vaccine used in LMICs. This complex formulation contained (1) vaccine antigens (i.e., whole-cell pertussis (wP), diphtheria (D), tetanus (T), Haemophilus influenza (Hib), and hepatitis B (HepB), (2) a mixture of aluminum-salt adjuvants (AH and Adju-Phos®, AP), and (3) a preservative (thimerosal, TH). Selective, stability-indicating competitive immunoassays were developed to monitor binding of specific mAbs to each antigen, except wP which required the setup of a mouse immunogenicity assay. Simple mixing led to the desorption of t-NRRV antigens from AH and increased degradation during storage. These deleterious effects were caused by specific antigens, AP, and TH. An AH-only pentavalent formulation mitigated t-NRRV antigen desorption; however, the Hib antigen displayed previously reported AH-induced instability. The same rank-ordering of t-NRRV antigen stability (P[8] > P[4] > P[6]) was observed in mock pentavalent formulations and with various preservatives. The lessons learned are discussed to enable future multidose, combination vaccine formulation development with new vaccine candidates.

Diphtheria toxin (DT) is the main virulence factor of Corynebacterium diphtheriae, C. ulcerans and C. pseudotuberculosis. Moreover, new Corynebacterium species with the potential to produce diphtheria toxin have also been described. Therefore, the detection of the toxin is the most important test in the microbiological diagnosis of diphtheria and other corynebacteria infections. Since the first demonstration in 1888 that DT is a major virulence factor of C. diphtheriae, responsible for the systemic manifestation of the disease, various methods for DT detection have been developed, but the diagnostic usefulness of most of them has not been confirmed on a sufficiently large group of samples. Despite substantial progress in the science and diagnostics of infectious diseases, the Elek test is still the basic recommended diagnostic test for DT detection. The challenge here is the poor availability of an antitoxin and declining experience even in reference laboratories due to the low prevalence of diphtheria in developed countries. However, recent and very promising assays have been developed with the potential for use as rapid point-of-care testing (POCT), such as ICS and LFIA for toxin detection, LAMP for tox gene detection, and biosensors for both.

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Corynebacterium diphtheriae is the causative agent of diphtheria, a severe respiratory disease in humans. C. diphtheriae colonizes the human upper respiratory tract, where it acquires zinc, an essential metal required for survival in the host. While the mechanisms for zinc transport by C. diphtheriae are not well characterized, four putative zinc ABC-type transporter loci were recently identified in strain 1737: iutABCD/E (iut), znuACB (znu), nikABCD1 (nik1), and nikABCD2 (nik2). A mutant deleted for all four loci (Δ4) exhibited similar growth to that of the wild-type strain in a zinc-limited medium, suggesting there are additional zinc transporters. Two additional gene loci predicted to be associated with metal import, mntABCD (mnt) and sidAB (sid), were deleted in the Δ4 mutant to construct a new mutant designated Δ6. The C. diphtheriae Δ6 mutant exhibited significantly reduced growth under zinc limitation relative to the wild type, suggesting a deficiency in zinc acquisition. Strains retaining the iut, znu, mnt, or sid loci grew to near-wild-type levels in the absence of the other five loci, indicating that each of these transporters may be involved in zinc uptake. Plasmid complementation with cloned iut, znu, mnt, or nik1 loci also enhanced the growth of the Δ6 mutant. Quantification of intracellular zinc content by inductively coupled plasma mass spectrometry was consistent with reduced zinc uptake by Δ6 relative to the wild type and further supports a zinc uptake function for the transporters encoded by iut, znu, and mnt. This study demonstrates that C. diphtheriae zinc transport is complex and involves multiple zinc uptake systems.IMPORTANCEZinc is a critical nutrient for all forms of life, including human bacterial pathogens. Thus, the tools that bacteria use to acquire zinc from host sources are crucial for pathogenesis. While potential candidates for zinc importers have been identified in Corynebacterium diphtheriae from gene expression studies, to date, no study has clearly demonstrated this function for any of the putative transporters. We show that C. diphtheriae encodes at least six loci associated with zinc import, underscoring the extent of redundancy for zinc acquisition. Furthermore, we provide evidence that a previously studied manganese-regulated importer can also function in zinc import. This study builds upon our knowledge of bacterial zinc transport mechanisms and identifies potential targets for future diphtheria vaccine candidates.

(1) Background: We aim to systematically review the current evidence on immunity against tetanus, diphtheria, and pertussis in adult solid organ transplantation (SOT) recipients, either through natural infection or vaccination. (2) Methods: This systematic review was conducted per PRISMA guidelines. We assessed the risk of bias using the Cochrane RoB 2 and ROBINS-I and summarized the findings narratively due to the heterogeneity of the studies. (3) Results: Of the 315 screened articles, 11 were included. Tetanus immunity varied between 55% and 86%, diphtheria immunity from 23% to 75%, and pertussis immunity was between 46% and 82%. Post-vaccination immunity showed variation across the studies, with some indicating reductions and others no change, with antibody responses influenced by transplanted organs, gender, age, and immunosuppressive regimens. The single randomized study exhibited a low risk of bias, while of the ten non-randomized studies, six showed moderate and four serious risks of bias, necessitating cautious interpretation of results. (4) Conclusions: SOT recipients exhibit considerable immunity against tetanus and diphtheria at transplantation, but this immunity decreases over time. Although vaccination can enhance this immunity, the response may be suboptimal, and the increased antibody levels may not persist, underscoring the need for tailored vaccination strategies in this vulnerable population.

Thailand has incorporated the whole-cell (wP) pertussis vaccine into the expanded program on immunization since 1977 and has offered the acellular pertussis (aP) vaccine as an optional vaccine for infants since 2001. We followed healthy children from a clinical trial (ClinicalTrials.gov NCT02408926) in which children were randomly assigned to receive either pentavalent (DTwP-HB-Hib) or hexavalent (DTaP-IPV-HB-Hib) vaccines for their primary series (administered at 2, 4, and 6 months) and first booster vaccination (18 months). Both groups received Tdap-IPV as a second booster at the age of 4 y. Blood samples were collected for evaluation of antibody persistence to diphtheria toxoid (DT), tetanus toxoid (TT), and Bordetella pertussis (B. pertussis) between 2 and 6 y of age annually, and for the immunogenicity study of Tdap-IPV at 1 month after the second booster. Antibody persistence to Haemophilus influenzae type b (Hib) was followed until 3 y of age. A total of 105 hexavalent-vaccinated children and 91 pentavalent-vaccinated children completed this study. Both pentavalent and hexavalent groups demonstrated increased antibody levels against DT, TT, and B. pertussis antigens following the second booster with Tdap-IPV. All children achieved a seroprotective concentration for anti-DT and anti-TT IgG at 1 month post booster. The hexavalent group possessed significantly higher anti-pertactin IgG (adjusted p = .023), whereas the pentavalent group possessed significantly higher anti-pertussis toxin IgG (adjusted p < .001) after the second booster. Despite declining levels post-second booster, a greater number of children sustained protective levels of anti-DT and anti-TT IgG compared to those after the first booster.

Objectives: To describe a suspected diphtheria outbreak in a Swiss asylum seeker reception centre, and to analyse its management response regarding testing and vaccination. Methods: We retrospectively analysed clinical, microbiology, and case management data of all asylum seekers tested for C. diphtheriae between 28th August and 31st December 2022 while residing at the centre. Results are reported descriptively. Results: Among 265 individuals tested, ten cases of cutaneous diphtheria, one simultaneous respiratory and cutaneous case, and nine respiratory carriers were identified. Mass throat screening, targeted throat testing and targeted wound testing yielded 4.8%, 4.3%, and 17.4% positive results, respectively. No respiratory carrier was identified among cutaneous cases undergoing a throat swab, and no symptomatic case was identified among individuals with unspecific throat symptoms. Rates of vaccination implementation of newly arriving asylum seekers before and after the outbreak were low (17.5% and 15.5%, respectively), as were rates of targeted vaccination among cases and close contacts. Conclusion: We provide evidence for transmission both prior to arrival and within the setting, suboptimal practices and timeliness of testing, and implementation gaps in vaccination.

In recent years, diphtheria has re-emerged in areas with inadequate vaccination coverage, and Europe has not been spared with several cases among migrants. Diphtheria is a potentially fatal infection caused mainly by toxigenic strains of Corynebacterium diphtheriae. Due to the high mortality rate, especially among young children, the fight against diphtheria is considered one of the first conquests of immunization. In the history of medicine, there is a unique case of an unconventional response to a diphtheria outbreak in which sled dogs were used to overcome the supply difficulties of diphtheria antitoxin. The mass media followed the medical response to the outbreak and raised audience awareness of public health issues. The facts of Nome, Alaska, in 1925 can serve as a catalyst to rethink conventional responses to diphtheria outbreaks in low-income countries today and promote mass media awareness of public health importance.

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Adhesive capsulitis following vaccination is a rare complication secondary to improper intramuscular (IM) deltoid vaccine administration. It is considered a subset of the broad category known as shoulder injury related to vaccine administration (SIRVA). SIRVA typically results from improper shoulder anatomic localization prior to injection, leading to erroneous placement of the needle into the glenohumeral joint capsule or subacromial space. This can trigger a wide array of pathologies, including adhesive capsulitis. We present the first known case of adhesive capsulitis following improper tetanus-diphtheria (Td) vaccine administration. The patient, a previously healthy middle-aged female, began experiencing significant anterior left shoulder pain the day following a Td booster vaccination. She remarked receiving the injection \"higher up\" in the shoulder than normal. Over the next two weeks, she began noting significant shoulder stiffness, which was followed by a progressive loss of shoulder range of motion. Her symptoms persisted for four months without definitive diagnosis or treatment. After four months of symptoms, the patient visited an outpatient sports medicine clinic where the diagnosis of adhesive capsulitis was made. Although the patient was referred for physical therapy, focusing on gentle range of motion (ROM) and stretches, followed by a planned isometric strengthening program once ROM improved, she was eventually lost to follow-up, and her recovery is unclear. Given the rarity of the diagnosis, it is unclear if adhesive capsulitis, secondary to improper IM vaccination, follows the same temporal course as \"classic\" adhesive capsulitis or results in a different timeframe of recovery. Further studies are needed on this subject.