scholarly journals A simian-adenovirus-vectored rabies vaccine suitable for thermostabilisation and clinical development for low-cost single-dose pre-exposure prophylaxis

2018 ◽  
Author(s):  
Chuan Wang ◽  
Pawan Dulal ◽  
Xiangyang Zhou ◽  
Zhiquan Xiang ◽  
Hooman Goharriz ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Single Dose ◽  
Rabies Virus ◽  
Low Cost ◽  
Rabies Vaccine ◽  
Human Rabies ◽  
Effective Population ◽  
Adenovirus Serotype ◽  
Simian Adenovirus ◽  
Exposure Prophylaxis

AbstractBackgroundEstimates of current global rabies mortality range from 26,000 to 59,000 deaths per annum. Although pre-exposure prophylaxis using inactivated rabies virus vaccines (IRVs) is effective, it requires two to three doses and is regarded as being too expensive and impractical for inclusion in routine childhood immunization programmes.Methodology/ Principal FindingsHere we report the development of a simian-adenovirus-vectored rabies vaccine intended to enable cost-effective population-wide pre-exposure prophylaxis against rabies. ChAdOx2 RabG uses the chimpanzee adenovirus serotype 68 (AdC68) backbone previously shown to achieve pre-exposure protection against rabies in non-human primates. ChAdOx2 differs from AdC68 in that it contains the human adenovirus serotype 5 (AdHu5) E4 orf6/7 region in place of the AdC68 equivalents, enhancing ease of manufacturing in cell lines which provide AdHu5 E1 proteinsin trans.We show that immunogenicity of ChAdOx2 RabG in mice is comparable to that of AdC68 RabG and other adenovirus serotypes expressing rabies virus glycoprotein. High titers of rabies virus neutralizing antibody (VNA) are elicited after a single dose. The relationship between levels of VNA activity and rabies glycoprotein monomer-binding antibody differs after immunization with adenovirus-vectored vaccines and IRV vaccines, suggesting routes to further enhancement of the efficacy of the adenovirus-vectored candidates. We also demonstrate that ChAdOx2 RabG can be thermostabilised using a low-cost method suitable for clinical bio-manufacture and ambient-temperature distribution in tropical climates. Finally, we show that a dose-sparing effect can be achieved by formulating ChAdOx2 RabG with a simple chemical adjuvant. This approach could lower the cost of ChAdOx2 RabG and other adenovirus-vectored vaccines.Conclusions/ SignificanceChAdOx2 RabG may prove to be a useful tool to reduce the human rabies death toll. We have secured funding for Good Manufacturing Practice-compliant bio-manufacture and Phase I clinical trial of this candidate.Author summaryRabies was, after smallpox, the second human disease for which an efficacious vaccine was developed, by Pasteur in 1885. Although it is eminently preventable, with highly efficacious vaccines available for both humans and animals, it still causes considerable mortality in low and middle-income countries. It is a particular problem in areas with the weakest healthcare and veterinary infrastructure, where achieving prompt post-exposure vaccination or high-coverage dog vaccination are challenging.Here, we report the development of a new candidate rabies vaccine, designed to enable low-cost single-dose pre-exposure human rabies prophylaxis in such settings. ChAdOx2 RabG is based upon a simian adenovirus-vectored candidate previously shown to achieve protection after a single dose in non-human primates, now modified to allow clinical-grade bio-manufacture. We show that it induces a potent immune response in mice, that this response can be further enhanced by clinically-relevant adjuvant, and that we can stabilise it such that it can withstand temperatures of up to 45 °C for a month. We will be performing a clinical trial of this candidate in the near future.

scholarly journals Human rabies post-exposure prophylaxis relative to the disease epidemiological status

2019 ◽  
Vol 24 (1) ◽  
pp. 315-322 ◽  
Author(s):  
Bruno Fonseca Martins da Costa Andrade ◽  
Taísa Santos de Melo Andrade ◽  
Luzia Helena Queiroz
Keyword(s):  
Rabies Vaccine ◽  
Human Rabies ◽  
Post Exposure Prophylaxis ◽  
Post Exposure ◽  
Paulo State ◽  
Technical Manual ◽  
Prophylactic Measures ◽  
Exposure Prophylaxis ◽  
Main City ◽  
Technical Recommendations

Abstract This study evaluated the prophylactic measures adopted after attacks by dogs and cats in the main city of Northwester São Paulo State, based on the technical manual for post-exposure treatment, considering the not controlled (1990-1996) and controlled (1997-2010) rabies status. A retrospective analysis was done using the data from the SINAN records (W64-CID10) between 1990 and 2010. In most cases, the accidents were mild (76.9%), and biting animals were healthy (75.4%); therefore, no treatment was needed in 53.3% of the cases. In 64.6% of cases, the prescribed PEP treatment was inappropriate. The most indicated PEP treatments consisted of vaccine and RIG (43.4%), and either three doses of mouse brain vaccine or two doses of cell culture vaccine (76.5%), during the not controlled and controlled rabies periods, respectively. The treatment was more appropriate and followed the technical recommendations during controlled rabies periods compared to not controlled (p < 0.0001) periods. However, excessive application of RIG and rabies vaccine was observed in both periods.

scholarly journals Current Rabies Vaccines Do Not Confer Protective Immunity against Divergent Lyssaviruses Circulating in Europe

Viruses ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 892 ◽  
Author(s):  
Juan E. Echevarría ◽  
Ashley C. Banyard ◽  
Lorraine M. McElhinney ◽  
Anthony R. Fooks
Keyword(s):  
Protective Immunity ◽  
Rabies Vaccine ◽  
Human Rabies ◽  
Post Exposure Prophylaxis ◽  
Efficient Tool ◽  
Imported Case ◽  
Health Authorities ◽  
European Health ◽  
Preventive Vaccination ◽  
Exposure Prophylaxis

The use of the rabies vaccine for post-exposure prophylaxis started as early as 1885, revealing a safe and efficient tool to prevent human rabies cases. Preventive vaccination is the basis for the control of canine-mediated rabies, which has already been eliminated from extensive parts of the world, including Europe. Plans to eliminate canine-mediated human rabies by 2030 have been agreed upon by international organisations. However, rabies vaccines are not efficacious against some divergent lyssaviruses. The presence in European indigenous bats of recently described lyssaviruses, which are not neutralised by antibody responses to existing vaccines, as well as the declaration of an imported case of an African lyssavirus, which also escapes vaccine-derived protection, leaves the European health authorities unable to provide efficacious protective vaccines to some potential situations of human exposure. All these circumstances highlight the need for a universal pan-lyssavirus rabies vaccine, able to prevent human rabies in all circumstances.

scholarly journals How geographic access to care shapes disease burden: the current impact of post-exposure prophylaxis and potential for expanded access to prevent human rabies deaths in Madagascar

2020 ◽  
Author(s):  
Malavika Rajeev ◽  
Hélène Guis ◽  
Glenn Edosoa ◽  
Chantal Hanitriniaina ◽  
Anjasoa Randrianarijaona ◽  
...  
Keyword(s):  
Rabies Vaccine ◽  
Human Rabies ◽  
Post Exposure Prophylaxis ◽  
Travel Times ◽  
Middle Income ◽  
Geographic Access ◽  
Post Exposure ◽  
Canine Rabies ◽  
Middle Income Countries ◽  
Exposure Prophylaxis

AbstractBackgroundPost-exposure prophylaxis (PEP) is highly effective at preventing human rabies deaths, however access to PEP is limited in many rabies endemic countries. The 2018 decision by Gavi to add human rabies vaccine to its investment portfolio should expand PEP availability and reduce rabies deaths. We explore how geographic access to PEP impacts the rabies burden in Madagascar and the potential benefits of improved provisioning.Methodology & Principal FindingsWe use travel times to the closest clinic providing PEP (N=31) as a proxy for access. We find that travel times strongly predict reported bite incidence across the country. Using resulting estimates in an adapted decision tree framework we extrapolate rabies deaths and reporting and find that geographic access to PEP shapes burden sub-nationally. We estimate 960 human rabies deaths annually (95% Prediction Intervals (PI):790 - 1120), with PEP averting an additional 800 deaths (95% PI: 800 (95% PI: 640 - 970) each year. Under these assumptions, we find that expanding PEP to one clinic per district could reduce deaths by 19%, but even with all major health centers provisioning PEP (1733 additional clinics), we still expect substantial rabies mortality. Our quantitative estimates are most sensitive to assumptions of underlying rabies exposure incidence, but qualitative patterns of the impacts of travel times and expanded PEP access are robust.Conclusions & SignificancePEP is effective at preventing rabies deaths, and in the absence of strong surveillance, targeting underserved populations may be the most equitable way to provision PEP. Our framework could be used to guide PEP expansion and improve targeting of interventions in similar endemic settings where PEP access is geographically restricted. While better PEP access should save many lives, improved outreach and surveillance is needed and if rolled out with Gavi investment could catalyze progress towards achieving zero rabies deaths.Author SummaryCanine rabies causes an estimated 60,000 deaths each year across the world, primarily in low- and middle-income countries where people have limited access to both human vaccines (post-exposure prophylaxis or PEP) and dog rabies vaccines. Given that we have the tools to prevent rabies deaths, a global target has been set to eliminate deaths due to canine rabies by 2030, and recently, Gavi, a multilateral organization that aims to improve access to vaccines in the poorest countries, added human rabies vaccine to it’s portfolio. In this study, we estimated reported bite incidence in relation to travel times to clinics provisioning PEP, and extrapolate human rabies deaths in Madagascar. We find that PEP currently averts around 800 deaths each year, but that the burden remains high (1000 deaths/ year), particularly in remote, hard-to-reach areas. We show that expanding PEP availability to more clinics could significantly reduce rabies deaths in Madagascar, but our results suggest that expansion alone will not eliminate deaths. Combining PEP expansion with outreach, surveillance, and mass dog vaccination programs will be necessary to move Madagascar, and other Low- and Middle-Income countries, forward on the path to rabies elimination.

scholarly journals Antigenic variants of rabies virus

1980 ◽  
Vol 152 (1) ◽  
pp. 99-112 ◽  
Author(s):  
TJ Wiktor ◽  
H Koprowski
Keyword(s):  
Rabies Virus ◽  
Rabies Vaccine ◽  
Human Rabies ◽  
Parent Virus ◽  
Antigenic Analysis ◽  
Challenge Virus ◽  
Antigenic Sites ◽  
Antigenic Relatedness ◽  
Glycoprotein Antigen ◽  
Selection Of

Antigenic variants of CVS-11 strain of rabies virus were selected after treatment of virus populations with monoclonal antibodies directed against the glycoprotein antigen of the virus. These variants resisted neutralization by the hybridoma antibody used for their selection. Two independently mutating antigenic sites could be distinguished when five variants were tested with nine hybridoma antibodies. The frequency of single epitope variants in a cloned rabies virus seed was approximately 1:10,000. Animals were not or only partially protected when challenged with the parent virus or with another variant, but were fully protected against challenge with the virus used for immunization. Variants were also detected among seven street viruses obtained from fatal cases of human rabies. Animals immunized with standard rabies vaccine were protected against challenge with some but not all street rabies variants. A comparative antigenic analysis between vaccine strain and challenge virus by means of monoclonal antiglycoprotein antibodies showed a slightly closer degree of antigenic relatedness between vaccine and challenge strain in the combinations where vaccination resulted in protection. It remains unknown, however, whether these apparently minor antigenic differences in the glycoproteins account for the varying degrees of protection. The results of this study clearly indicate that the selection of vaccine strains and the methods used to evaluate the potency of rabies vaccines need to be revised.

scholarly journals Human exposure to potential rabies virus transmitters in Olinda, State of Pernambuco, between 2002 and 2006

2007 ◽  
Vol 40 (6) ◽  
pp. 617-621 ◽  
Author(s):  
Filipe Dantas-Torres ◽  
Edmilson Ferreira de Oliveira-Filho
Keyword(s):  
Rabies Virus ◽  
Human Exposure ◽  
Nonhuman Primates ◽  
Prophylactic Treatment ◽  
Human Rabies ◽  
Post Exposure Prophylaxis ◽  
Wild Animals ◽  
Health Unit ◽  
Multifaceted Approach ◽  
Exposure Prophylaxis

The aim of the present study was to evaluate the data on human exposure to potential rabies virus transmitters in Olinda, State of Pernambuco, Brazil. Data from 7,062 patients who underwent antirabies prophylactic treatment in Olinda between 2002 and 2006 were analyzed. As expected, dogs and cats were involved in most of the cases; i.e. 82.3 and 16.3%, respectively. Attacks by nonhuman primates, bats and other species (unspecified) were also reported. Among the 7,062 patients who underwent antirabies treatment, 582 patients abandoned the treatment, either by indication from the health unit (195) or by their own decision (387). In conclusion, this study has indicated that prophylaxis for human rabies in this urban area will require a multifaceted approach, including health education, post-exposure prophylaxis, systematic vaccination for dogs and cats, and possibly selective control over wild animals such as hematophagous bats.

scholarly journals Purified chick embryo cell rabies vaccine: economical multisite intradermal regimen for post-exposure prophylaxis

1987 ◽  
Vol 99 (3) ◽  
pp. 755-765 ◽  
Author(s):  
Pravan Suntharasamai ◽  
M. J. Warrell ◽  
Chaisin Viravan ◽  
Pornthep Chanthavanich ◽  
Sornchai Looareesuwan ◽  
...  
Keyword(s):  
Chick Embryo ◽  
Embryo Cell ◽  
Rabies Vaccine ◽  
Human Rabies ◽  
Post Exposure Prophylaxis ◽  
Protective Efficiency ◽  
Vaccine Regimen ◽  
Post Exposure ◽  
Chick Embryo Cell ◽  
Exposure Prophylaxis

SUMMARYThe standard six-dose intramuscular (i.m.) rabies post-exposure vaccine regimen using a new purified chick embryo cell (PCEC) vaccine was compared with two economical multisite intradermal (i.d.) PCEC regimens, a multisite i.m. PCEC schedule and a subcutaneous regimen using a suckling mouse brain (SMB) rabies vaccine manufactured in Thailand. The neutralizing antibody results for the four-site and eight-site i.d. and the standard i.m. PCEC regimens were similar over 3 months. A three-site i.m. PCEC regimen had no advantage. The SMB vaccine gave the lowest antibody levels. Human rabies immune globulin therapy significantly increased the GMT of all groups on day 7, unlike equine antirabies serum (EARS). Both antisera suppressed antibody responses to PCEC on days 14 and 28. Three generalized reactions probably related to EARS were the only serious side effects. An eight-site i.d. PCEC vaccine regimen proved as immunogenic as the routine i.m. schedule and, if implemented as post-exposure prophylaxis, would be the cheapest widely available tissue culture vaccine regimen. The protective efficiency should now be tested in patients bitten by rabid animals.

scholarly journals Single-Dose Protection against Plasmodium berghei by a Simian Adenovirus Vector Using a Human Cytomegalovirus Promoter Containing Intron A

2008 ◽  
Vol 82 (8) ◽  
pp. 3822-3833 ◽  
Author(s):  
S. Sridhar ◽  
A. Reyes-Sandoval ◽  
S. J. Draper ◽  
A. C. Moore ◽  
S. C. Gilbert ◽  
...  
Keyword(s):  
Single Dose ◽  
Immune Responses ◽  
Human Cytomegalovirus ◽  
Plasmodium Berghei ◽  
Neutralizing Antibodies ◽  
Adenovirus Vector ◽  
Adenoviral Vectors ◽  
Effector Memory ◽  
Adenovirus Serotype ◽  
Simian Adenovirus

ABSTRACT Human adenovirus serotype 5 (AdH5) vector vaccines elicit strong immune responses to the encoded antigen and have been used in various disease models. We designed AdH5 vectors expressing antigen under the control of a human cytomegalovirus (HCMV) immediate-early promoter containing its intron A sequence. The transcriptional levels of antigen and immune responses to antigen for vectors with the HCMV promoter with the intron A sequence (LP) were greater than those for AdH5 vectors using the HCMV promoter sequence without intron A (SP). We compared an E1E3-deleted AdH5 adenoviral vector, which affords more space for insertion of foreign sequences, and showed it to be as immunogenic as an E1-deleted AdH5 vector. Neutralizing antibodies to AdH5 limit the efficacy of vaccines based on the AdH5 serotype, and simian adenoviral vectors offer an attractive option to overcome this problem. We constructed E1E3-deleted human and simian adenoviral vectors encoding the pre-erythrocytic-stage malarial antigen Plasmodium berghei circumsporozoite protein. We compared the immunogenicity and efficacy of AdC6, a recombinant simian adenovirus serotype 6 vector, in a murine malaria model to those of AdH5 and the poxviral vectors MVA and FP9. AdC6 induced sterile protection from a single dose in 90% of mice, in contrast to AdH5 (25%) and poxviral vectors MVA and FP9 (0%). Adenoviral vectors maintained potent CD8+ T-cell responses for a longer period after immunization than did poxviral vectors and mainly induced an effector memory phenotype of cells. Significantly, AdC6 was able to maintain protection in the presence of preexisting immunity to AdH5.

scholarly journals Portable Rabies Virus Sequencing in Canine Rabies Endemic Countries Using the Oxford Nanopore MinION

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1255
Author(s):  
Crystal M. Gigante ◽  
Gowri Yale ◽  
Rene Edgar Condori ◽  
Niceta Cunha Costa ◽  
Nguyen Van Long ◽  
...  
Keyword(s):  
Rabies Virus ◽  
Rural Areas ◽  
Low Cost ◽  
High Volume ◽  
Human Rabies ◽  
Valuable Insight ◽  
Canine Rabies ◽  
Virus Diversity ◽  
Oxford Nanopore ◽  
International Border

As countries with endemic canine rabies progress towards elimination by 2030, it will become necessary to employ techniques to help plan, monitor, and confirm canine rabies elimination. Sequencing can provide critical information to inform control and vaccination strategies by identifying genetically distinct virus variants that may have different host reservoir species or geographic distributions. However, many rabies testing laboratories lack the resources or expertise for sequencing, especially in remote or rural areas where human rabies deaths are highest. We developed a low-cost, high throughput rabies virus sequencing method using the Oxford Nanopore MinION portable sequencer. A total of 259 sequences were generated from diverse rabies virus isolates in public health laboratories lacking rabies virus sequencing capacity in Guatemala, India, Kenya, and Vietnam. Phylogenetic analysis provided valuable insight into rabies virus diversity and distribution in these countries and identified a new rabies virus lineage in Kenya, the first published canine rabies virus sequence from Guatemala, evidence of rabies spread across an international border in Vietnam, and importation of a rabid dog into a state working to become rabies-free in India. Taken together, our evaluation highlights the MinION’s potential for low-cost, high volume sequencing of pathogens in locations with limited resources.

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