Hepatitis B Virus Infection in Vaccinated Children and Adolescents with HBsAg-positive Parents: Is Routine Vaccination Sufficient?

Background: Hepatitis B virus (HBV) is a severe public health problem in Iran. This study was conducted to investigate the intrafamilial transmission of HBV in vaccinated children whose one or both parents were positive for hepatitis B surface antigen (HBsAg). Methods: In a study with retrospective cohort design, 110 exposed cases with HBsAg-positive parent(s) were compared with 110 unexposed controls of the same sex and age groups. The participants were directly asked about demographic characteristics, medical history, and vaccinations. Blood samples were collected and analyzed for HBV infection markers using the ELIZA method. Results: Overall, 1.8% HBsAg (P = 0.15) and 13.6% hepatitis B core antibody (HBcAb) (P < 0.0001) positivity rates were detected in the exposed group. The hepatitis B surface antibody titer (HBsAb) showed that 34.5% of cases and 56.3% of controls had HBsAb levels > 10 IU/L. There was a significant difference in the protective HBsAb level between the two groups (P < 0.0001). There were significant associations between HBsAb level and gender in the exposed group and decreased HBsAb levels and age. Conclusions: The high rate of positive HBcAb and HBsAg and decreasing HBsAb levels with age in this study indicate that routine childhood vaccination programs are inadequate in preventing HBV transmission and vaccine routes changing or further booster vaccination is essential. Effective case finding in vaccinated children with HBsAg-positive parents, intradermal vaccination, and hepatitis B immunoglobulin in newborns with HBsAg-positive fathers are suggested.

Efficacy of Needle-Less Intradermal Vaccination against Porcine Epidemic Diarrhea Virus

To prevent diarrhea in suckling piglets infected by porcine epidemic diarrhea virus (PEDV), porcine epidemic diarrhea (PED) vaccines are administered mainly through intramuscular (IM) or oral routes. We found that growing pigs vaccinated with an inactivated PEDV vaccine via the intradermal (ID) route had higher neutralizing antibody titers and cytokine (IFN-γ, IL-4, and IL-10) levels than non-vaccinated pigs. In addition, suckling piglets acquired lactogenic immunity from pregnant sows inoculated with an ID PED vaccine. We evaluated the efficacy of vaccination via this route, along with subsequent protection against virulent PEDV. At six days post-challenge, the survival rate of suckling piglets exposed to virulent PEDV was 70% for the ID group and 0% for the mock group (no vaccine). At necropsy, villi length in the duodenum and ileum of piglets with lactogenic immunity provided by ID-vaccinated sows proved to be significant (p < 0.05) when compared with those in piglets from mock group sows. Thus, vaccination using an inactivated PED vaccine via the ID route provides partial protection against infection by virulent PEDV.

Intradermal vaccination of live attenuated influenza vaccine protects mice against homologous and heterologous influenza challenges

We previously developed a temperature-sensitive, and NS1 gene deleted live attenuated influenza vaccine (DelNS1-LAIV) and demonstrated its potent protective efficacy in intranasally vaccinated mice. Here we investigated whether intradermal (i.d.) vaccination induces protective immunity. Our results showed that DelNS1-LAIV intradermal vaccination conferred effective and long-lasting protection against lethal virus challenge in mice. A single intradermal injection of DelNS1-LAIV conferred 100% survival with no weight loss in mice after A(H1N1)09 influenza virus (H1N1/415742Md) challenge. DelNS1-LAIV injection resulted in a significant reduction of lung viral load and reduced airway epithelial cell death and lung inflammatory cytokine responses at day 2 and 4 post challenge. Full protections of mice lasted for 6 months after immunization. In vitro infection of DelNS1-LAIV in monocyte-derived dendritic cells (MoDCs) demonstrated activation of antigen-presenting cells at 33 °C, together with the results of abortive replication of DelNS1-LAIV in skin tissue and strong upregulation of inflammatory cytokines/chemokines expression, our results suggested the strong immunogenicity of this vaccine. Further, we demonstrate that the underlying protection mechanism induced by intradermal DelNS1-LAIV is mainly attributed to antibody responses. Together, this study opens up an alternative route for the administration of LAIV, which may benefit individuals not suitable for intranasal LAIV immunization.

Smallpox vaccination induces a substantial increase in commensal skin bacteria that promote pathology and enhance immunity

Interactions between pathogens, host microbiota and the immune system influence many physiological and pathological processes. In the 20 th century, widespread dermal vaccination with vaccinia virus (VACV) led to the eradication of smallpox but how VACV interacts with the microbiota and whether this influences the efficacy of vaccination are largely unknown. Here we report that intradermal vaccination with VACV induces a large increase in the number of commensal bacteria in infected tissue, which enhance recruitment of inflammatory cells, promote tissue damage and increase immunity. Treatment of vaccinated specific-pathogen-free (SPF) mice with antibiotic, or infection of genetically-matched germ-free (GF) animals caused smaller lesions without alteration in virus titre. Tissue damage correlated with enhanced neutrophil and T cell infiltration and levels of pro-inflammatory tissue cytokines and chemokines. One month after vaccination, GF mice had reduced VACV-neutralising antibodies compared to SPF mice; while numbers of VACV-specific CD8 + T cells were equal in all groups of animals. Thus, skin microbiota may provide an adjuvant-like stimulus during vaccination with VACV. This observation has implications for dermal vaccination with live vaccines.

Tolerability, safety and immunogenicity of intradermal delivery of a fractional dose mRNA -1273 SARS-CoV-2 vaccine in healthy adults as a dose sparing strategy

Background There is an urgent need for fair and equitable access to safe and effective vaccines to end the COVID-19 pandemic. Shortages in reagents and vaccines are a major challenge, as well as limited knowledge on dose response relationship with mRNA COVID-19 vaccines. We explored intradermal fractional dose administration of a mRNA SARS-CoV-2/COVID-19 vaccine as a potential dose-sparing strategy. Methods We conducted a proof-of-concept, dose-escalation, open-label, randomised-controlled vaccine trial (IDSCOVA) in healthy adults aged 18-30 years. To test initial safety, ten participants received 10 μg mRNA-1273 vaccine through intradermal injection at day 1 and 29. Following a favourable safety review, thirty participants were 1:1 randomised to receive 20 μg mRNA-1273 either intradermally or intramuscularly. The primary endpoint was tolerability and safety. The secondary endpoint was seroconversion and specific IgG concentration against SARS-CoV-2 spike S1 and Receptor Binding Domain (RBD) after the second dose at day 43. We compared results to two historical cohorts of non-hospitalised COVID-19 patients and vaccinated individuals. Findings Thirty-eight of forty included participants (median age 25 years) completed the study. There were no serious adverse events. Self-reported local adverse reactions after intradermal delivery were mild, both in the 10 μg and the 20 μg group. In the higher dose group, systemic adverse reactions were more common, but still well tolerated. All 38 participants mounted substantially higher IgG-anti-S1 and IgG-anti-RBD concentrations at day 43 than COVID-19 controls. At day 43, anti-S1 (95% CI) was 1,696 (1,309-2,198) BAU/mL for the 10 μg intradermal group, 1,406 (953.5-2,074) BAU/mL for the 20 μg intramuscular group and 2,057 (1,421-2,975) BAU/mL for the 20 μg intradermal group. Anti-S1 was 107.2 (63-182.2) BAU/mL for the convalescent plasma control group and 1,558 (547.8-4,433) BAU/mL for the individuals vaccinated with 100 μg mRNA-1273. Interpretation Intradermal administration of 10 μg and 20 μg mRNA-1273 vaccine was well tolerated and safe, and resulted in a robust antibody response. Intradermal vaccination has the potential to be deployed for vaccine dose-sparing.

Efficacy of Simultaneous Intradermal Vaccination of Swine against Porcine Circovirus 2, Porcine Reproductive and Respiratory Syndrome Virus, Mycoplasma hyopneumoniae and Lawsonia intracellularis

The combined application of vaccines in swine offers many benefits, including reduced time and labour costs, and improved animal welfare, due to fewer injections and manipulations. This study investigated if simultaneous intradermal vaccinations against porcine circovirus 2, porcine reproductive and respiratory syndrome virus, Mycoplasma hyopneumoniae, and Lawsonia intracellularis, using a specialised needle-free applicator would confer comparable protection against experimental infection compared to the single vaccines. In all cases, the administration of the vaccines together was as efficacious as the administration of the vaccines alone, significantly reducing clinical signs associated with each of the four pathogens.

Vaccination with BCGΔBCG1419c protects against pulmonary and extrapulmonary TB and is safer than BCG

A single intradermal vaccination with an antibiotic-less version of BCGΔBCG1419c given to guinea pigs conferred a significant improvement in outcome following a low dose aerosol exposure to M. tuberculosis compared to that provided by a single dose of BCG Pasteur. BCGΔBCG1419c was more attenuated than BCG in murine macrophages, athymic, BALB/c, and C57BL/6 mice. In guinea pigs, BCGΔBCG1419c was at least as attenuated as BCG and induced similar dermal reactivity to that of BCG. Vaccination of guinea pigs with BCGΔBCG1419c resulted in increased anti-PPD IgG compared with those receiving BCG. Guinea pigs vaccinated with BCGΔBCG1419c showed a significant reduction of M. tuberculosis replication in lungs and spleens compared with BCG, as well as a significant reduction of pulmonary and extrapulmonary tuberculosis (TB) pathology measured using pathology scores recorded at necropsy. Evaluation of cytokines produced in lungs of infected guinea pigs showed that BCGΔBCG1419c significantly reduced TNF-α and IL-17 compared with BCG-vaccinated animals, with no changes in IL-10. This work demonstrates a significantly improved protection against pulmonary and extrapulmonary TB provided by BCGΔBCG1419c in susceptible guinea pigs together with an increased safety compared with BCG in several models. These results support the continued development of BCGΔBCG1419c as an effective vaccine for TB.

MTBVAC vaccination protects rhesus macaques against aerosol challenge with M. tuberculosis and induces immune signatures analogous to those observed in clinical studies

A single intradermal vaccination with MTBVAC given to adult rhesus macaques was well tolerated and conferred a significant improvement in outcome following aerosol exposure to M. tuberculosis compared to that provided by a single BCG vaccination. Vaccination with MTBVAC resulted in a significant reduction in M. tuberculosis infection-induced disease pathology measured using in vivo medical imaging, in gross pathology lesion counts and pathology scores recorded at necropsy, the frequency and severity of pulmonary granulomas and the frequency of recovery of viable M. tuberculosis from extrapulmonary tissues following challenge. The immune profiles induced following immunisation with MTBVAC reflect those identified in human clinical trials of MTBVAC. Evaluation of MTBVAC- and TB peptide-pool-specific T-cell cytokine production revealed a predominantly Th1 response from poly- (IFN-γ+TNF-α+IL2+) and multi-(IFN-γ+TNF-α+) functional CD4 T cells, while only low levels of Th22, Th17 and cytokine-producing CD8 T-cell populations were detected together with low-level, but significant, increases in CFP10-specific IFN-γ secreting cells. In this report, we describe concordance between immune profiles measured in clinical trials and a macaque pre-clinical study demonstrating significantly improved outcome after M. tuberculosis challenge as evidence to support the continued development of MTBVAC as an effective prophylactic vaccine for TB vaccination campaigns.