Rabies virus causes lethal brain infection in about 61000 people per year. Each year, tens of thousands of people receive anti-rabies prophylaxis with plasma-derived immunoglobulins and vaccine soon after exposure. Anti-rabies immunoglobulins are however expensive and have limited availability. VHH are the smallest antigen-binding functional fragments of camelid heavy chain antibodies, also called Nanobodies. The therapeutic potential of anti-rabies VHH was examined in a mouse model using intranasal challenge with a lethal dose of rabies virus. Anti-rabies VHH were administered directly into the brain or systemically, by intraperitoneal injection, 24 hours after virus challenge. Anti-rabies VHH were able to significantly prolong survival or even completely rescue mice from disease. The therapeutic effect depended on the dose, affinity and brain and plasma half-life of the VHH construct. Increasing the affinity by combining two VHH with a glycine-serine linker into bivalent or biparatopic constructs, increased the neutralizing potency to the picomolar range. Upon direct intracerebral administration, a dose as low as 33 µg of the biparatopic Rab-E8/H7 was still able to establish an anti-rabies effect. The effect of systemic treatment was significantly improved by increasing the half-life of Rab-E8/H7 through linkage with a third VHH targeted against albumin. Intraperitoneal treatment with 1.5 mg (2505 IU, 1 ml) of anti-albumin Rab-E8/H7 prolonged the median survival time from 9 to 15 days and completely rescued 43% of mice. For comparison, intraperitoneal treatment with the highest available dose of human anti-rabies immunoglobulins (65 mg, 111 IU, 1 ml) only prolonged survival by 2 days, without rescue. Overall, the therapeutic benefit seemed well correlated with the time of brain exposure and the plasma half-life of the used VHH construct. These results, together with the ease-of-production and superior thermal stability, render anti-rabies VHH into valuable candidates for development of alternative post exposure treatment drugs against rabies.
Post-exposure prophylaxis (PEP) against rabies infection consists of a combination of passive immunisation with plasma-derived human or equine immune globulins and active immunisation with vaccine delivered shortly after exposure. Since anti-rabies immune globulins are expensive and scarce, there is a need for cheaper alternatives that can be produced more consistently. Previously, we generated potent virus-neutralising VHH, also called Nanobodies, against the rabies glycoprotein that are effectively preventing lethal disease in an in vivo mouse model. The VHH domain is the smallest antigen-binding functional fragment of camelid heavy chain-only antibodies that can be manufactured in microbial expression systems. In the current study we evaluated the efficacy of half-life extended anti-rabies VHH in combination with vaccine for PEP in an intranasal rabies infection model in mice. The PEP combination therapy of systemic anti-rabies VHH and intramuscular vaccine significantly delayed the onset of disease compared to treatment with anti-rabies VHH alone, prolonged median survival time (35 versus 14 days) and decreased mortality (60% versus 19% survival rate), when treated 24 hours after rabies virus challenge. Vaccine alone was unable to rescue mice from lethal disease. As reported also for immune globulins, some interference of anti-rabies VHH with the antigenicity of the vaccine was observed, but this did not impede the synergistic effect. Post exposure treatment with vaccine and human anti-rabies immune globulins was unable to protect mice from lethal challenge. Anti-rabies VHH and vaccine act synergistically to protect mice after rabies virus exposure, which further validates the possible use of anti-rabies VHH for rabies PEP.
MALT1 is involved in the activation of immune responses, as well as in the proliferation and survival of certain cancer cells. MALT1 acts as a scaffold protein for NF-κB signaling and a cysteine protease that cleaves substrates, further promoting the expression of immunoregulatory genes. Deregulated MALT1 activity has been associated with autoimmunity and cancer, implicating MALT1 as a new therapeutic target. Although MALT1 deficiency has been shown to protect against experimental autoimmune encephalomyelitis, nothing is known about the impact of MALT1 on virus infection in the central nervous system. Here, we studied infection with an attenuated rabies virus, Evelyn-Rotnycki-Abelseth (ERA) virus, and observed increased susceptibility with ERA virus in MALT1−/− mice. Indeed, after intranasal infection with ERA virus, wild-type mice developed mild transient clinical signs with recovery at 35 days postinoculation (dpi). Interestingly, MALT1−/− mice developed severe disease requiring euthanasia at around 17 dpi. A decreased induction of inflammatory gene expression and cell infiltration and activation was observed in MALT1−/− mice at 10 dpi compared to MALT1+/+ infected mice. At 17 dpi, however, the level of inflammatory cell activation was comparable to that observed in MALT1+/+ mice. Moreover, MALT1−/− mice failed to produce virus-neutralizing antibodies. Similar results were obtained with specific inactivation of MALT1 in T cells. Finally, treatment of wild-type mice with mepazine, a MALT1 protease inhibitor, also led to mortality upon ERA virus infection. These data emphasize the importance of early inflammation and activation of T cells through MALT1 for controlling the virulence of an attenuated rabies virus in the brain.IMPORTANCE Rabies virus is a neurotropic virus which can infect any mammal. Annually, 59,000 people die from rabies. Effective therapy is lacking and hampered by gaps in the understanding of virus pathogenicity. MALT1 is an intracellular protein involved in innate and adaptive immunity and is an interesting therapeutic target because MALT1-deregulated activity has been associated with autoimmunity and cancers. The role of MALT1 in viral infection is, however, largely unknown. Here, we study the impact of MALT1 on virus infection in the brain, using the attenuated ERA rabies virus in different models of MALT1-deficient mice. We reveal the importance of MALT1-mediated inflammation and T cell activation to control ERA virus, providing new insights in the biology of MALT1 and rabies virus infection.
Implementation of this two-dose schedule will protect more people against Rabies. Travelers and military personnel under time constraints, who otherwise would remain unvaccinated, can be considered adequately protected after this two-dose schedule. For populations in endemic areas, local application of a two-dose schedule could provide an opportunity to vaccinate more people with less vaccine. Given the paucity of published data, this study adds relevant evidence in support of the new policy (2017) of WHO, concerning a two-dose, seven-day schedule is approved for all healthy individuals.
Background Effective and safe single-visit rabies vaccination for pre- and postexposure prophylaxis (PrEP and PEP) could substantially simplify rabies prevention and therefore increase compliance. Methods In a comparative trial, 303 healthy adults received a primary vaccination that consisted of 2 intradermal (ID) doses of 0.1 mL of the purified chicken embryo cell vaccine (PCEV) during a single visit. One year later, participants were randomly assigned to receive either 4 or 2 ID PEP booster doses of 0.1 mL PCEV during a single visit. The primary endpoint for immunogenicity was the percentage of participants with an adequate antibody level (>0.5 IU/mL) 7 days after the booster doses. The safety endpoint was the proportion of participants who developed adverse events (AEs) following primary and/or booster vaccination. Results All participants, except 1 (99.3%) in each study group, had a rabies antibody titer >0.5 IU/mL on day 7 following the booster schedules. Participants exposed to the 4-dose PEP schedule had a geometric mean titer of 20 IU/mL vs 14 IU/mL for the 2-dose PEP schedule (P = .0228). Local reactions at the injection site following PrEP and PEP were mild and transient and only seen in 14.9% and 49.6%–53% of the participants, respectively. No serious AEs were reported. Conclusions In healthy adults, a 2-dose (2 × 0.1 mL) single-visit ID PEP schedule was as immunologically adequate and safe as a 4-dose (4 × 0.1 mL) single-visit PEP schedule 7 to 28 months following a 2-dose (2 × 0.1 mL) single-visit ID PREP. Clinical Trials Registration EudraCT 2014-00183612.
Background A number of tick-borne pathogens circulate in the Belgian tick population in addition to the causative agent of Lyme borreliosis. However, so far, only a few patients with tick-borne diseases other than Lyme borreliosis have been reported in Belgium. The aim of this study was to investigate the occurrence of other human tick-borne infections in Belgium and their possible clinical manifestation. Methods Patients with fever (> 37.5 °C) after a tick bite or those with erythema migrans (EM) were included in the study. EDTA-blood samples were screened for the presence of DNA from Borrelia burgdorferi sensu lato, Borrelia miyamotoi, Anaplasma phagocytophilum, Neoehrlichia mikurensis, spotted fever group rickettsiae (genus Rickettsia), Babesia spp., Bartonella spp., Spiroplasma ixodetis and tick-borne encephalitis virus, using multiplex PCR methods. A questionnaire on, among others, demographics and clinical symptoms, was also filled in. Results Over a period of 3 years, 119 patients with EM and 14 patients with fever after a recent tick bite were enrolled in the study. Three samples initially tested positive for N. mikurensis by quantitative PCR (qPCR), but the results could not be confirmed by other PCR methods, and repetition of the DNA extraction procedure and qPCR test was not successful. The qPCR test results for the other tick-borne pathogens were negative. Conclusions In general, only a few patients with fever after a tick bite could be identified. Although no tick-borne pathogens were detected, their occurrence cannot be excluded based on the limited number of patients and the limitations inherent to current methodologies. This study underscores the possibility of false-positive PCR results and the necessity for the development of multiple independent tools for the sensitive and specific detection of emerging tick-borne pathogens. Graphical Abstract
Background To date, published data regarding long-lasting immunological rabies memory after a pre-exposure prophylaxis (PrEP)-schedule are scarce. We tested the hypothesis that rabies booster immunization elicits rapid anamnestic responses. Methods For this observational study, we included participants who had received PrEP 10-24 years before inclusion. We measured rabies antibody titers before, and on days 3, 7 and 14 after one single intramuscular booster. Results All 28 participants responded adequately regardless route of administration or (2-dose vs. 3-dose) PrEP-regimen. Conclusion Rabies immunological memory is reactivated within 7 days after a single intramuscular booster immunization, even when administered 10-24 years after PrEP.
Background: For immunocompromised patients (ICPs), administration of rabies immunoglobulins (RIG) after exposure is still recommended regardless of prior vaccination, due to a lack of data. We aimed to assess the one-year boostability of a 3-dose rabies pre-exposure prophylaxis (PrEP) schedule in individuals using immunosuppressive monotherapy. Methods: In this prospective study, individuals on immunosuppressive monotherapy with a conventional immunomodulator (cIM) or a TNF-alpha inhibitor (TNFi) for a chronic inflammatory disease received a 3-dose intramuscular PrEP schedule (days 0,7,21–28) with 1 mL Rabipur®, followed by a 2-dose simulated post-exposure prophylaxis (PEP) schedule (days 0,3) after 12 months. Rabies neutralizing antibodies were assessed at baseline, on Day 21–28 (before 3rd PrEP dose), Day 60, Month 12 and Month 12 + 7 days. The primary outcome was one-year boostability, defined as the proportion of patients with a neutralizing antibody titre of ≥ 0.5 IU/mL at Month 12 + 7 days. Secondary outcomes were geometric mean titres and factors associated with the primary endpoint. Results: We included 56 individuals, of whom 52 completed the study. The one-year boostability was 90% (47/52) with a GMT of 6.16 (95% CI 3.83–9.91). All participants seroconverted at some point in the study. Early response to PrEP (at day 21–28) was significantly associated with 100% boostability (Odds ratio 51; 95% confidence interval [5.0–6956], p < 0.01). The vaccination schedule was safe and well tolerated. No vaccine-related serious adverse events occurred. Conclusion: In patients using immunosuppressive monotherapy, a 3-dose rabies PrEP schedule followed by a 2-dose PEP schedule is immunogenic, with all patients seroconverting at some point in the study. Although boostability 7 days after PEP was not 100%, nobody would wrongly be denied RIG when only administered to those who responded early to PrEP, while reducing administration of RIG by 73%.
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