Dupilumab does not affect correlates of vaccine-induced immunity: A randomized, placebo-controlled trial in adults with moderate-to-severe atopic dermatitis.

BACKGROUND: The impact of dupilumab, an anti-interleukin (IL) 4 receptor α antibody that inhibits IL-4 and IL-13 signaling, on vaccine responses of patients with atopic dermatitis (AD) is unknown. OBJECTIVES: To assess T-cell-dependent and T-cell-independent humoral immune responses to tetanus and meningococcal vaccines, IgE seroconversion to tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccination, and dupilumab efficacy and safety. METHODS: In a randomized, double-blinded, placebo-controlled study (NCT02210780), adults with moderate-to-severe AD received dupilumab (300 mg) or placebo weekly for 16 weeks, and single doses of Tdap and quadrivalent meningococcal polysaccharide vaccines at week 12. Primary endpoint was proportion of patients achieving satisfactory IgG response to tetanus toxoid at week 16. RESULTS: In total, 178 patients completed the study. Similar positive immune responses (≥4-fold increase in antibody titer, or an antibody titer of ≥8) were achieved in the dupilumab and placebo groups to tetanus (83.3% and 83.7%, respectively) and meningococcal polysaccharide (86.7% and 87.0%, respectively). Dupilumab significantly decreased total serum IgE; most dupilumab-treated patients were Tdap-IgE seronegative at week 32 (62.2% dupilumab and 34.8% placebo). Dupilumab improved key AD efficacy endpoints (P < .001). Injection-site reactions and conjunctivitis were more common with dupilumab; AD exacerbations more frequent with placebo. LIMITATION: Patients' prior vaccination status was not available before enrollment. CONCLUSION: Dupilumab did not affect responses to the vaccines studied, significantly decreased IgE, and improved measures of AD severity versus placebo, with an acceptable safety profile.

Preclinical and clinical experience with dupilumab on the correlates of live attenuated vaccines.

Background: The safety and tolerability of live attenuated vaccines in patients administered dupilumab for moderate-to-severe asthma have not been previously evaluated. During the LIBERTY ASTHMA TRAVERSE open-label extension study (ClinicalTrials.gov identifier NCT02134028), a yellow fever outbreak in Brazil required administration of a live attenuated vaccine to at-risk individuals. Objective: Our aim was to evaluate immune response to a live attenuated vaccine in the context of IL-4 receptor blockade (REGN1103, a dupilumab surrogate) in mice and in dupilumab-treated patients with moderate-to-severe asthma who participated in TRAVERSE. Methods: In the preclinical study, mice were coadministered REGN1103/isotype control and live attenuated influenza vaccine/control, followed by influenza virus challenge. During TRAVERSE, 37 patients discontinued dupilumab treatment and were administered 17D live attenuated yellow fever vaccine (YFV). Safety and tolerability data, dupilumab serum concentrations, and plaque reduction neutralization titers before and after vaccination were collected. Results: In the preclinical study, there was no impact of REGN1103 on vaccine efficacy in mice. In TRAVERSE, all 37 patients who received YFV achieved seroprotection despite most having therapeutic levels of dupilumab, with the magnitude of response appearing unrelated to prevaccination dupilumab concentrations. No instances of vaccine-related adverse events or vaccine hypersensitivity were reported in 36 patients; 1 patient reported nonserious body ache, malaise, and dizziness 7 days after vaccination but recovered fully. Conclusion: The preclinical model suggested that dupilumab does not affect the efficacy of live attenuated influenza vaccine. The live attenuated YFV did not raise safety concerns and appeared to be well tolerated in patients with asthma who recently discontinued dupilumab treatment, and dupilumab concentrations had no apparent impact on immunologic response to the vaccine.

Boosting of SARS-CoV-2 immunity in nonhuman primates using an oral rhabdoviral vaccine.

An orally active vaccine capable of boosting SARS-CoV-2 immune responses in previously infected or vaccinated individuals would help efforts to achieve and sustain herd immunity. Unlike mRNA-loaded lipid nanoparticles and recombinant replication-defective adenoviruses, replicating vesicular stomatitis viruses with SARS-CoV-2 spike glycoproteins (VSV-SARS2) were poorly immunogenic after intramuscular administration in clinical trials. Here, by G protein trans-complementation, we generated VSV-SARS2(+G) virions with expanded target cell tropism. Compared to parental VSV-SARS2, G-supplemented viruses were orally active in virus-naive and vaccine-primed cynomolgus macaques, powerfully boosting SARS-CoV-2 neutralizing antibody titers. Clinical testing of this oral VSV-SARS2(+G) vaccine is planned.

A system-view of Bordetella pertussis booster vaccine responses in adults primed with whole-cell versus acellular vaccine in infancy.

The increased incidence of whooping cough worldwide suggests that current vaccination against Bordetella pertussis infection has limitations in quality and duration of protection. The resurgence of infection has been linked to the introduction of acellular vaccines (aP), which have an improved safety profile compared with the previously used whole-cell (wP) vaccines. To determine immunological differences between aP and wP priming in infancy, we performed a systems approach of the immune response to booster vaccination. Transcriptomic, proteomic, cytometric, and serologic profiling revealed multiple shared immune responses with different kinetics across cohorts, including an increase of blood monocyte frequencies and strong antigen-specific IgG responses. Additionally, we found a prominent subset of aP-primed individuals (30%) with a strong differential signature, including higher levels of expression for CCL3, NFKBIA, and ICAM1. Contrary to the wP individuals, this subset displayed increased PT-specific IgE responses after boost and higher antigen-specific IgG4 and IgG3 antibodies against FHA and FIM2/3 at baseline and after boost. Overall, the results show that, while broad immune response patterns to Tdap boost overlap between aP- and wP-primed individuals, a subset of aP-primed individuals present a divergent response. These findings provide candidate targets to study the causes and correlates of waning immunity after aP vaccination.

Generation of IL-3-Secreting CD4+ T Cells by Microbial Challenge at Skin and Mucosal Barriers.

During Ag priming, naive CD4+ T cells differentiate into subsets with distinct patterns of cytokine expression that dictate to a major extent their functional roles in immune responses. We identified a subset of CD4+ T cells defined by secretion of IL-3 that was induced by Ag stimulation under conditions different from those associated with previously defined functional subsets. Using mouse models of bacterial and viral infections, we showed that IL-3-secreting CD4+ T cells were generated by infection at the skin and mucosa but not by infections introduced directly into the blood. Most IL-3-producing T cells coexpressed GM-CSF and other cytokines that define multifunctionality. Generation of IL-3-secreting T cells in vitro was dependent on IL-1 family cytokines and was inhibited by cytokines that induce canonical Th1 or Th2 cells. Our results identify IL-3-secreting CD4+ T cells as a potential functional subset that arises during priming of naive T cells in specific tissue locations.

Th1/Th17 polarization persists following whole-cell pertussis vaccination despite repeated acellular boosters.

In the mid-1990s, whole-cell pertussis (wP) vaccines were associated with local and systemic adverse events that prompted their replacement with acellular pertussis (aP) vaccines in many high-income countries. In the past decade, rates of pertussis disease have increased in children receiving only aP vaccines. We compared the immune responses to aP boosters in individuals who received their initial doses with either wP or aP vaccines using activation-induced marker (AIM) assays. Specifically, we examined pertussis-specific memory CD4+ T cell responses ex vivo, highlighting a type 2/Th2 versus type 1/Th1 and Th17 differential polarization as a function of childhood vaccination. Remarkably, after a contemporary aP booster, cells from donors originally primed with aP were (a) associated with increased IL-4, IL-5, IL-13, IL-9, and TGF-ß and decreased IFN-γ and IL-17 production, (b) defective in their ex vivo capacity to expand memory cells, and (c) less capable of proliferating in vitro. These differences appeared to be T cell specific, since equivalent increases of antibody titers and plasmablasts after aP boost were seen in both groups. In conclusion, our data suggest that there are long-lasting effects and differences in polarization and proliferation of T cell responses in adults originally vaccinated with aP compared with those that initially received wP, despite repeated acellular boosters.

HSV-2 ΔgD elicits FcγR-effector antibodies that protect against clinical isolates.

A single-cycle herpes simplex virus (HSV) deleted in glycoprotein D (ΔgD-2) elicited high titer HSV-specific antibodies (Abs) that (i) were rapidly transported into the vaginal mucosa; (ii) elicited antibody-dependent cell-mediated cytotoxicity but little neutralization; (iii) provided complete protection against lethal intravaginal challenge; and (iv) prevented establishment of latency in mice. However, clinical isolates may differ antigenically and impact vaccine efficacy. To determine the breadth and further define mechanisms of protection of this vaccine candidate, we tested ΔgD-2 against a panel of clinical isolates in a murine skin challenge model. The isolates were genetically diverse, as evidenced by genomic sequencing and in vivo virulence. Prime and boost immunization (s.c.) with live but not heat- or UV-inactivated ΔgD-2 completely protected mice from challenge with the most virulent HSV-1 and HSV-2 isolates. Furthermore, mice were completely protected against 100 times the lethal dose that typically kills 90% of animals (LD90) of a South African isolate (SD90), and no latent virus was detected in dorsal root ganglia. Immunization was associated with rapid recruitment of HSV-specific FcγRIII- and FcγRIV-activating IgG2 Abs into the skin, resolution of local cytokine and cellular inflammatory responses, and viral clearance by day 5 after challenge. Rapid clearance and the absence of latent virus suggest that ΔgD-2 elicits sterilizing immunity.

Multipurpose prevention technologies: the future of HIV and STI protection.

Every day, more than 1 million people are newly infected with sexually transmitted infections (STIs) that can lead to morbidity, mortality, and an increased risk of human immunodeficiency virus (HIV) acquisition. Existing prevention and management strategies, including behavior change, condom promotion, and therapy have not reduced the global incidence and prevalence, pointing to the need for novel innovative strategies. This review summarizes important issues raised during a satellite session at the first HIV Research for Prevention (R4P) conference, held in Cape Town, on October 31, 2014. We explore key STIs that are challenging public health today, new biomedical prevention approaches including multipurpose prevention technologies (MPTs), and the scientific and regulatory hurdles that must be overcome to make combination prevention tools a reality.