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Rhode Island Medical Journal (2013) Aug 2020Rabies is an acute encephalitis that is caused by rabies virus (RABV) infection, which belongs to the Rhabdoviridae family of viruses. It causes about 59,000 human... (Review)
Review
Rabies is an acute encephalitis that is caused by rabies virus (RABV) infection, which belongs to the Rhabdoviridae family of viruses. It causes about 59,000 human deaths per year (although this number may be under-reported) and is generally fatal, once signs and symptoms begin to appear. Rabies is still very prevalent and under- reported, particularly in low to middle-income countries such as Asia and Africa, where there is lack of access to healthcare and domestic dogs are not widely vaccinated. Although not commonplace in the USA, rabies is mostly transmitted by wild animals such as bats, raccoons, skunks and foxes. Domesticated cats and dogs are also at risk of acquiring rabies, if they have not been vaccinated. Larger carnivores, such as coyotes, bobcats, mountain lions, wolves, bears, woodchucks, and beavers, should also be considered rabid (unless proven otherwise) if they are involved in an unprovoked attack on a person. The rabies vaccine can prevent 99% of deaths if administered promptly after exposure. There are two main vaccination strategies for rabies prevention: pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP). This article reviews background and epidemiology of rabies and current guidelines for rabies PrEP and PEP regimens for the United States.
Topics: Animals; Animals, Domestic; Animals, Wild; Centers for Disease Control and Prevention, U.S.; Disease Reservoirs; Humans; Population Surveillance; Rabies; Rabies Vaccines; United States; Vaccination; Zoonoses
PubMed: 32752569
DOI: No ID Found -
Revue Scientifique Et Technique... Aug 2018Current rabies vaccines are safe and, when administered properly, they are highly effective. In addition, they elicit long-lasting immunity, with virus-neutralising... (Review)
Review
Current rabies vaccines are safe and, when administered properly, they are highly effective. In addition, they elicit long-lasting immunity, with virus-neutralising antibody titres persisting for years after vaccination. However, current regimens require multiple doses to achieve high neutralising titres and they are costly, which means that it is difficult for developing countries, where rabies deaths are highest, to implement widespread vaccination. New innovations are the only way to reduce rabies disease to acceptable rates. Numerous preclinical and clinical studies are under way, testing novel vaccines, adjuvants and injection methods. Research into the use of live vaccines and alternative vaccine vectors is ongoing, while attempts to develop DNA vaccines have so far failed to match the immunogenicity and neutralising capability of traditional vaccines. The development of molecular adjuvants that induce faster, stronger immune responses with less antigen has yielded exciting preclinical results and appears to edge us closer to a better rabies vaccine. However, steep challenges remain: molecular adjuvants require administration with live vaccines, and differences in species specificity of immune molecules complicate development. Over all, the array of research undertaken over the past decade is impressive and encouraging, but most new vaccines have yet to be tested in clinical trials, and the viability of such experimental vaccines in the global market remains to be seen. Only a vaccine that outperforms currently available vaccines in every area will have a chance at widespread adoption. Nevertheless, the authors are confident that some vaccine candidates will meet these criteria.
Topics: Animals; Antibodies, Viral; Humans; Rabies; Rabies Vaccines; Vaccination
PubMed: 30747119
DOI: 10.20506/rst.37.2.2831 -
Nature Medicine Jan 2021Most of what we know about adaptive immunity has come from inbred mouse studies, using methods that are often difficult or impossible to confirm in humans. In addition,...
Most of what we know about adaptive immunity has come from inbred mouse studies, using methods that are often difficult or impossible to confirm in humans. In addition, vaccine responses in mice are often poorly predictive of responses to those same vaccines in humans. Here we use human tonsils, readily available lymphoid organs, to develop a functional organotypic system that recapitulates key germinal center features in vitro, including the production of antigen-specific antibodies, somatic hypermutation and affinity maturation, plasmablast differentiation and class-switch recombination. We use this system to define the essential cellular components necessary to produce an influenza vaccine response. We also show that it can be used to evaluate humoral immune responses to two priming antigens, rabies vaccine and an adenovirus-based severe acute respiratory syndrome coronavirus 2 vaccine, and to assess the effects of different adjuvants. This system should prove useful for studying critical mechanisms underlying adaptive immunity in much greater depth than previously possible and to rapidly test vaccine candidates and adjuvants in an entirely human system.
Topics: Adjuvants, Immunologic; B-Lymphocytes; COVID-19 Vaccines; Germinal Center; Hemagglutinin Glycoproteins, Influenza Virus; Humans; In Vitro Techniques; Influenza Vaccines; Lymphoid Tissue; Measles-Mumps-Rubella Vaccine; Organoids; Palatine Tonsil; Rabies Vaccines; T-Lymphocytes
PubMed: 33432170
DOI: 10.1038/s41591-020-01145-0 -
Human Vaccines & Immunotherapeutics Dec 2022Rabies is a highly fatal zoonotic disease caused by the rabies virus invading the central nervous system. When suspected of exposure to the rabies virus, post-exposure... (Review)
Review
Rabies is a highly fatal zoonotic disease caused by the rabies virus invading the central nervous system. When suspected of exposure to the rabies virus, post-exposure prophylaxis should be administered as soon as possible. Monoclonal antibodies (mAbs) neutralizing the rabies virus could be better in human rabies post-exposure prophylaxis than equine or human rabies immune globulin in terms of supply, cost, and efficacy. This article reviews anti-rabies mAbs produced by multiple techniques, and the results of clinical trials for anti-rabies mAbs cocktails recognizing non-overlapping epitopes are also discussed.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; Antibodies, Viral; Antineoplastic Agents, Immunological; Horses; Neutralization Tests; Post-Exposure Prophylaxis; Rabies; Rabies Vaccines; Rabies virus
PubMed: 35172707
DOI: 10.1080/21645515.2022.2026713 -
Virology Journal Nov 2022Rabies is a lethal zoonotic disease that is mainly caused by the rabies virus (RABV). Although effective vaccines have long existed, current vaccines take both time and...
Rabies is a lethal zoonotic disease that is mainly caused by the rabies virus (RABV). Although effective vaccines have long existed, current vaccines take both time and cost to produce. Messenger RNA (mRNA) technology is an emergent vaccine platform that supports rapid vaccine development on a large scale. Here, an optimized mRNA vaccine construct (LVRNA001) expressing rabies virus glycoprotein (RABV-G) was developed in vitro and then evaluated in vivo for its immunogenicity and protective capacity in mice and dogs. LVRNA001 induced neutralizing antibody production and a strong Th1 cellular immune response in mice. In both mice and dogs, LVRNA001 provided protection against challenge with 50-fold lethal dose 50 (LD) of RABV. With regards to protective efficiency, an extended dosing interval (14 days) induced greater antibody production than 3- or 7-day intervals in mice. Finally, post-exposure immunization against RABV was performed to evaluate the survival rates of dogs receiving two 25 μg doses of LVRNA001 vs. five doses of inactivated vaccine over the course of three months. Survival rate in the LVRNA001 group was 100%, whereas survival rate in the inactivated vaccine control group was only 33.33%. In conclusion, these results demonstrated that LVRNA001 induced strong protective immune responses in mice and dogs, which provides a new and promising prophylactic strategy for rabies.
Topics: Dogs; Mice; Animals; Rabies Vaccines; Rabies; RNA, Messenger; Antibodies, Viral; Rabies virus; Vaccines, Inactivated; Antibody Formation; mRNA Vaccines
PubMed: 36371169
DOI: 10.1186/s12985-022-01919-7 -
Nature Communications Jun 2023Licensed rabies virus vaccines based on whole inactivated virus are effective in humans. However, there is a lack of detailed investigations of the elicited immune...
Licensed rabies virus vaccines based on whole inactivated virus are effective in humans. However, there is a lack of detailed investigations of the elicited immune response, and whether responses can be improved using novel vaccine platforms. Here we show that two doses of a lipid nanoparticle-formulated unmodified mRNA vaccine encoding the rabies virus glycoprotein (RABV-G) induces higher levels of RABV-G specific plasmablasts and T cells in blood, and plasma cells in the bone marrow compared to two doses of Rabipur in non-human primates. The mRNA vaccine also generates higher RABV-G binding and neutralizing antibody titers than Rabipur, while the degree of somatic hypermutation and clonal diversity of the response are similar for the two vaccines. The higher overall antibody titers induced by the mRNA vaccine translates into improved cross-neutralization of related lyssavirus strains, suggesting that this platform has potential for the development of a broadly protective vaccine against these viruses.
Topics: Animals; Humans; Rabies; Rabies Vaccines; Broadly Neutralizing Antibodies; RNA, Messenger; Antibodies, Viral; Rabies virus; Glycoproteins
PubMed: 37349310
DOI: 10.1038/s41467-023-39421-5 -
The Lancet. Infectious Diseases Dec 2022Malaria is a leading cause of morbidity and mortality worldwide. We previously reported the efficacy of the R21/Matrix-M malaria vaccine, which reached the WHO-specified... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and immunogenicity of R21/Matrix-M vaccine against clinical malaria after 2 years' follow-up in children in Burkina Faso: a phase 1/2b randomised controlled trial.
BACKGROUND
Malaria is a leading cause of morbidity and mortality worldwide. We previously reported the efficacy of the R21/Matrix-M malaria vaccine, which reached the WHO-specified goal of 75% or greater efficacy over 12 months in the target population of African children. Here, we report the safety, immunogenicity, and efficacy results at 12 months following administration of a booster vaccination.
METHODS
This double-blind phase 1/2b randomised controlled trial was done in children aged 5-17 months in Nanoro, Burkina Faso. Eligible children were enrolled and randomly assigned (1:1:1) to receive three vaccinations of either 5 μg R21/25 μg Matrix-M, 5 μg R21/50 μg Matrix-M, or a control vaccine (the Rabivax-S rabies vaccine) before the malaria season, with a booster dose 12 months later. Children were eligible for inclusion if written informed consent could be provided by a parent or guardian. Exclusion criteria included any existing clinically significant comorbidity or receipt of other investigational products. A random allocation list was generated by an independent statistician by use of block randomisation with variable block sizes. A research assistant from the University of Oxford, independent of the trial team, prepared sealed envelopes using this list, which was then provided to the study pharmacists to assign participants. All vaccines were prepared by the study pharmacists by use of the same type of syringe, and the contents were covered with an opaque label. Vaccine safety, efficacy, and a potential correlate of efficacy with immunogenicity, measured as anti-NANP antibody titres, were evaluated over 1 year following the first booster vaccination. The population in which the efficacy analyses were done comprised all participants who received the primary series of vaccinations and a booster vaccination. Participants were excluded from the efficacy analysis if they withdrew from the trial within the first 2 weeks of receiving the booster vaccine. This trial is registered with ClinicalTrials.gov (NCT03896724), and is continuing for a further 2 years to assess both the potential value of additional booster vaccine doses and longer-term safety.
FINDINGS
Between June 2, and July 2, 2020, 409 children returned to receive a booster vaccine. Each child received the same vaccination for the booster as they received in the primary series of vaccinations; 132 participants received 5 μg R21 adjuvanted with 25 μg Matrix-M, 137 received 5 μg R21 adjuvanted with 50 μg Matrix-M, and 140 received the control vaccine. R21/Matrix-M had a favourable safety profile and was well tolerated. Vaccine efficacy remained high in the high adjuvant dose (50 μg) group, similar to previous findings at 1 year after the primary series of vaccinations. Following the booster vaccination, 67 (51%) of 132 children who received R21/Matrix-M with low-dose adjuvant, 54 (39%) of 137 children who received R21/Matrix-M with high-dose adjuvant, and 121 (86%) of 140 children who received the rabies vaccine developed clinical malaria by 12 months. Vaccine efficacy was 71% (95% CI 60 to 78) in the low-dose adjuvant group and 80% (72 to 85) in the high-dose adjuvant group. In the high-dose adjuvant group, vaccine efficacy against multiple episodes of malaria was 78% (95% CI 71 to 83), and 2285 (95% CI 1911 to 2568) cases of malaria were averted per 1000 child-years at risk among vaccinated children in the second year of follow-up. Among these participants, at 28 days following their last R21/Matrix-M vaccination, titres of malaria-specific anti-NANP antibodies correlated positively with protection against malaria in both the first year of follow-up (Spearman's ρ -0·32 [95% CI -0·45 to -0·19]; p=0·0001) and second year of follow-up (-0·20 [-0·34 to -0·06]; p=0·02).
INTERPRETATION
A booster dose of R21/Matrix-M at 1 year following the primary three-dose regimen maintained high efficacy against first and multiple episodes of clinical malaria. Furthermore, the booster vaccine induced antibody concentrations that correlated with vaccine efficacy. The trial is ongoing to assess long-term follow-up of these participants and the value of further booster vaccinations.
FUNDING
European and Developing Countries Clinical Trials Partnership 2 (EDCTP2), Wellcome Trust, and NIHR Oxford Biomedical Research Centre.
TRANSLATION
For the French translation of the abstract see Supplementary Materials section.
Topics: Humans; Rabies Vaccines; Burkina Faso; Follow-Up Studies; Malaria; Double-Blind Method; Adjuvants, Immunologic; Immunogenicity, Vaccine
PubMed: 36087586
DOI: 10.1016/S1473-3099(22)00442-X -
Cell Host & Microbe Sep 2022Rabies virus (RABV) causes lethal encephalitis and is responsible for approximately 60,000 deaths per year. As the sole virion-surface protein, the rabies virus...
Rabies virus (RABV) causes lethal encephalitis and is responsible for approximately 60,000 deaths per year. As the sole virion-surface protein, the rabies virus glycoprotein (RABV-G) mediates host-cell entry. RABV-G's pre-fusion trimeric conformation displays epitopes bound by protective neutralizing antibodies that can be induced by vaccination or passively administered for post-exposure prophylaxis. We report a 2.8-Å structure of a RABV-G trimer in the pre-fusion conformation, in complex with two neutralizing and protective monoclonal antibodies, 17C7 and 1112-1, that recognize distinct epitopes. One of these antibodies is a licensed prophylactic (17C7, Rabishield), which we show locks the protein in pre-fusion conformation. Targeted mutations can similarly stabilize RABV-G in the pre-fusion conformation, a key step toward structure-guided vaccine design. These data reveal the higher-order architecture of a key therapeutic target and the structural basis of neutralization by antibodies binding two key antigenic sites, and this will facilitate the development of improved vaccines and prophylactic antibodies.
Topics: Antibodies, Monoclonal; Antibodies, Neutralizing; Antibodies, Viral; Epitopes; Glycoproteins; Humans; Membrane Proteins; Rabies; Rabies Vaccines; Rabies virus
PubMed: 35985336
DOI: 10.1016/j.chom.2022.07.014 -
Revue Scientifique Et Technique... Aug 2018
Topics: Animals; Global Health; Humans; One Health; Rabies; Rabies Vaccines; Zoonoses
PubMed: 30747147
DOI: 10.20506/rst.37.2.2803 -
CMAJ : Canadian Medical Association... Jan 2018
Topics: Animals; Anti-Bacterial Agents; Bites and Stings; Dogs; Facial Injuries; Genitalia; Humans; Post-Exposure Prophylaxis; Rabies; Rabies Vaccines; Tetanus; Tetanus Toxoid
PubMed: 29378871
DOI: 10.1503/cmaj.170684