Zoonotic infections (also called zoonoses or anthropozoonotic infections) are human diseases acquired from a vertebrate animal. As a matter of fact, all arthropod-borne diseases with an animal host belong to the group of zoonotic infections, whether yellow fever, West Nile fever, Japanese encephalitis, tick-borne encephalitis or Rift Valley fever, to only name a few. Zoonotic infections also include haemorragic fevers such as EBOLA or Marburg, which primarily infect bats and secondarily African apes, Lassa fever and South American haemorragic fevers due to arenaviruses, which affect specific rodents, Nipah viral encephalitis, which is harbored in bats and may cause a lethal bronchopneumonia in pigs, as well as avian influenza (H5N1). They also include SARS, leptospirosis, plague, anthrax, and many other parasitic, viral and bacterial zoonoses. Several of these diseases are newly emerged and the general perception of their public health significance extends far beyond their actual incidence, due to their extremely high case fatality rate (60% for avian influenza, 50% for Nipah, 50% to 90% for EBOLA outbreaks). Many zoonotic infections actually are promoted by human behavior such as bush-meat hunting (EBOLA fever), the farming and trade of live wild animals (SARS), close and repeated contacts with infected animals (avian influenza), deforestation, which brings humans closer to infected vectors and animal reservoirs (leishmaniasis), or building of dams, that favors the proliferation of mosquitoes (Rift Valley fever). It is probable that bush-meat hunting was at the origin of HIV/AIDS
. Rabies remains a major public health problem in the world's poorest areas, especially in Africa and South and South-East Asia, where most human cases follow stray dog bites.
This chapter will focus on rabies, anthrax, whose interest was renewed when used as a bioterrorism agent, plague, and hepatitis E, an acute viral hepatitis with a high case fatality rate in pregnant women whose most likely reservoir is pigs. Rift Valley Fever is another zoonotic infection with an important, albeit geographically limited, impact.
Anthrax, a deadly zoonotic disease due to Bacillus anthracis, has been known since antiquity
. The fifth and sixth plagues in the Bible's book of Exodus may have been outbreaks of anthrax in cattle and humans. Naturally occurring anthrax in humans is acquired from contact with anthrax-infected animals or anthrax-contaminated animal products, which allows one to distinguish agricultural anthrax, a most significant problem in developing countries especially among veterinarians, agricultural workers and butchers, and industrial anthrax, resulting from exposure to contaminated sheep wool or goat hair that are processed into yarns used in the textile and carpet industry, as well as cattle hides that are processed into leather goods, or bones used for the manufacture of gelatin and/or fertilizer.
Anthrax infection in humans occurs by three major routes, the skin, the respiratory tract or the gastro-intestinal tract, generating three different primary forms of the disease, the cutaneous, the inhalational and the gastro-intestinal forms  . Cutaneous anthrax presents as a small pruritic papule that develops within a week into a vesicle usually on an exposed part of the body such as the face, the neck or arm. Edema and erythema often develop around the lesion. The vesicle eventually ruptures, revealing a depressed ulcer crater that develops into a black eschar. The case fatality rate of cutaneous anthrax usually is about 20% if untreated. Inhalational anthrax presents within one to five days with nonspecific symptoms, fatigue, myalgia and slight fever, which are followed by a sudden severe respiratory distress with dyspnea, cyanosis, and stridor leading to a lethal shock syndrome associated with pulmonary haemorrhage and mediastinal edema. Systemic infection with B anthracis resulting from inhalation causes a 100% case fatality rate. As to gastrointestinal anthrax, it develops within 2 to 5 days following ingestion of contaminated meat with nausea, vomiting, fever, abdominal pain and diarrhoea, eventually leading to toxemia, shock and death in 25% to 75% of cases.
The incidence of natural anthrax in industrialized countries remains quite low and the disease is not a major public health problem in the world. Thus, between 1900 and 2005, only 82 cases of inhalational anthrax were reported in the USA . Occasional anthrax epidemics nevertheless did occur, such as the Zimbabwe epidemic in the early 1980s with approximately 10 000 cases reported. The scene changed in 2001 with the bioweapon attacks in the Eastern USA. Modelling studies showed that anthrax spores used as a bioweapon against civilian populations could generate catastrophic consequences  . It was for example estimated that the airborne delivery of 50 kgs of anthrax spores over a large city could lead to 125 000 severe clinical cases of anthrax and 95 000 deaths. This renewed the general interest for the field and prompted the development of new anthrax vaccines.
Control of anthrax in humans and animals is based on control measures in livestock in endemic areas, such as the safe disposal of anthrax carcasses and vaccination of at-risk cattle herds. Incineration of carcasses is a manner to prevent contamination of the surrounding soil. Local conditions in many endemic countries however make these simple control measures difficult to implement. In industrializaed countries, prevention lies in good agricultural and industriual hygiene.
B anthracis, the agent of anthrax, is a large gram-positive, spore-forming, nonmotile bacillus with little if any genetic variability. In tissues, the bacteria are encapsulated and appear singly or in short chains of a few bacilli. The spores are extremely resistant in the environment and may survive for decades in certain soil conditions. They eventually are ingested by cattle or wild animals such as deer
 when grazing on contaminated land.
B anthracis has two major virulence factors that are carried by two distinct plasmids, pX01 which carries the tripartite toxin genes cya (edema factor), lef (lethal factor) and pagA (protective antigen), and pX02, which carries the gene encoding the polyglutamate capsular filaments. The tripartite exotoxin consists of the 83 kD protective antigen (PA), the 90 kD lethal factor (LF), and the 89 kD edema factor (EF)  . PA binds to cellular receptors and mediates the entry into the cytosol of both LF, a Zn+ metalloprotease that cleaves mitogen-activated protein kinase kinases (MAPK), and EF, an adenylate cyclase that converts ATP to cyclic AMP (cAMP) and promotes lethal tissue edema   . The lethal toxin is composed of PA combined with LF while the edema toxin is made from the combination of PA and EF. Both LF and EF inhibit acquired and innate immune responses, allowing the bacteria to replicate unchecked in the host .
The polyglutamate capsule plays a major role as an invasiveness factor. Bacteria which lack plasmid pX02 and therefore are uncapsulated are attenuated for animals and can be used as live attenuated vaccines, as initially demonstrated by Sterne    (For a review, see ).
Anthrax vaccines are available for both animals and humans. However, in humans, their use has been confined to high-risk groups such as occupationally exposed workers and military personnel.
A few live attenuated B anthracis strains have been developed as vaccines, such as the uncapsulated Sterne strain for subcutaneous immunization of domestic animals or the uncapsulated SST-1 strain used in Russia and the Langzhou avirulent strain A16R developed in China. The latter are given by skin scarification as a single or a double immunization followed by yearly booster immunizations .
The human anthrax vaccine licensed in the USA is made from cell-free filtrates of bacterial cultures of an unencapsulated, nonvirulent strain of B. anthracis adsorbed to aluminium hydroxide (Anthrax Vaccine Adsorbed/BioThrax, Emergent BioSolutions Inc).   . To develop and maintain protective immunity in humans, these vaccines must be administered subcutaneously six times over 18 months, followed by yearly booster injections   . A recent study showed that by using the IM route of immunization rather than the SC route, effective immuninization required a three-dose schedule rather than the original four-dose schedule  . Still, these vaccines have shown only partial protection from infection with some strains of B. anthracis in animal models  . After the intentional release of anthrax spores in 2001, it was clear that a more effective, easily administered, and safer vaccine was needed for emergency situations     for both pre- and post-exposure prophylaxis.
While the poly-D-glutamic acid capsule is nonimmunogenic  , the PA component of the toxin has been shown to induce a protective antibody response in numerous studies using animal models of infection     and including inhalational anthrax  . Recent research has focused on the design of a recombinant PA (rPA) vaccine which would eliminate the need for filtered culture supernatants or whole B. anthracis lysates, as well as produce a more consistent immune response. Thus, rPA given to healthy adults in two IM injections four weeks apart with the adjuvant alhydrogel was well tolerated and highly immunogenic  . PA is the main component of the two licensed anthrax vaccines, Anthrax Vaccine Adsorbed (AVA) in the USA and Anthrax Vaccine Precipitated (AVP) in the UK.
Several new human adjuvants have been studied to be included in anthrax vaccines, including monophosphorylated lipid A (MPL A), saponin QS-21, and muramyl tripeptide linked with dipalmitol phosphatidylethanolamine. In recent attempts at developing mucosal anthrax vaccines a variety of other adjuvants were tested including soy phosphatidyl choline, cholera toxin (CT), and CpG oligonucleotides   . The use of soybean oil-and-water nanoemulsions (NEs) (NanoBio Corporation, Ann Arbor, MI) as a mucosal adjuvant appears very promising: the candidate vaccine generated long-term, high-titer neutralizing anti-PA IgAs and IgGs in mucosal secretions and provided significant protection of the animals against intranasal challenge with B anthracis spores after only two intranasal immunizations .
Live recombinant anthrax vaccines using bacterial or vaccinia virus vectors are also being developed, as well as recombinant HBc particles expressing a PA epitope   . The demonstration that spore components could offer additional protection in animal models has moreover lead to the development of a dual component candidate anthrax vaccine that combines rPA with formaldehyde-inactivated spores and was shown to be significantly protective against intra-nasal spore challenge in mice  . In a similar approach, PA was combined with LF and poly-gamma-glutamic acid (gamma PDGA) and administered by the intra nasal route in mice, inducing high level protective bactericidal antibodies  . Similarly, a trivalent vaccine composed of rPA added with inactivated LF and EF induced long-lasting protective immunity in rabbits .
Hepatitis E was first identified as an acute non-A non-B viral hepatitis. It has since been recognized as a major cause of acute hepatitis in young adults throughout much of Asia, Africa and Latin America
. The disease is endemic in many parts of the world, including the Indian subcontinent, northwest China, and the Central Asian Republics. In these regions, HEV is transmitted predominantly through the fecal-oral route, especially through the consumption of fecally contaminated drinking water. In India, the lifetime infection risk is more than 60%, which translates into hundreds of thousands of cases annually
. The highest rates of infection occur in regions with poorest sanitation. A minor mode of transmission could be through blood transfusion
High prevalence of anti-HEV antibodies has been reported in blood donors from non-endemic regions    , which could be due to zoonotic transmission of the virus. HEV-related viruses have been found in pigs    , deer  , and wild boar  as well as in rodents and chickens  . Direct transmission has been reported from animals to humans through consumption of undercooked deer meat  or uncooked liver from a wild boar  . Humans who consume contaminated pork products or are involved in the rearing of pigs are potentially at risk of HEV infection   .
HEV infection occurs mostly in young to middle age adult population, i.e. between the ages of 15 and 40 years. The presence of anti-HEV antibodies has been detected in only less than 5% of children under the age of 10, contrary to what is observed with HAV infection. Clinical symptoms of hepatitis E are typical of acute viral hepatitis including jaundice, abdominal pain, fever and hepatomegaly lasting 1 to 4 weeks. The existence of a chronic form of HEV infection has recently been reported in organ transplant recipients  . In rare cases, patients may present with severe disease progressing to fatal liver failure. This is mostly observed in chronic liver patients  and in pregnant women in their third trimester, who often develop encephalopathy with cerebral edema and disseminated intravascular coagulation   . The case fatality rate among these women may be as high as 25%, whereas it only is 0.2% to 1% in the general population   . The selective suppression of NFkB p65 in pregnant women, causing liver degeneration, severe immunodeficiency and multi-organ failure has been suggested  but the precise cellular/molecular mechanisms involved are not clear.
HEV is a small (32-34 nm in diameter), spherical, nonenveloped virus with a 7.2 kb positive-sense, 5'-capped single-stranded RNA genome. It belongs to the genus Hepevirus in the Hepeviridae family. Its molecular organization, deduced from the cloning and sequencing of the genome
, shows a high degree of sequence conservation among isolates from different origin. At least four phylogenetically distinct HEV genotypes have been defined
, although all HEV strains share at least one major serologically cross-reactive epitope, so that they all belong to the same serotype. Genotype 1 includes Asian and African human HEV strains, genotype 2 includes a Mexican and African strains. Genotype 4 is prevalent in Western industrialized countries whereas genotype 3 is mostly found in Far Eastern Asian countries. Outbreaks due to HEV genotype 1 or 2 are the results of efficient human-to-human fecal-oral transmission. In contrast, genotypes 3 and 4 are prevalent in domestic animals such as swine, and only occasionally infect humans, probably due to less efficient cross-species transmission.
The HEV genome includes three partially overlapping open reading frames (ORF). ORF1 encodes a large nonstructural protein with methyltransferase, cysteine protease, RNA helicase and RNA polymerase activities. ORF 2 encodes the 660 amino acid long viral capsid protein, and ORF3 encodes a 123 aminoacid protein which seems to interact with various intracellular pathways to create an environment favorable for virus replication. The capsid protein of HEV (pORF2) is glycosylated. The glycosylation seems to be required for the production of infectious viral particles and replication in macaques .
Since there is no robust system to grow HEV in cell culture, inactivated or live attenuated vaccines were considered as not feasible until recently
, when the successful replication of a genotype 3 HEV isolate was obtained in PLC/PRF/5 cells from nonhuman primate origin
The available HEV vaccine is made of a 56 kD pORF2 segment protein (genotype 1). The truncated protein produced in insect cells using a recombinant baculovirus efficiently self-assembles into virus-like particles (VLPs) that expose the dominant HEV neutralization epitope
and elicit a protective antibody response in a monkey challenge model
. Cynomolgous monkeys were successfully protected against challenge by passive immunization with human convalescent serum or by active immunization with the ORF2 VLP vaccine. These results prompted a randomized clinical trial of the vaccine's efficacy in volunteers from the Nepalese Army, a population at high risk for hepatitis E
. The VLP vaccine was administered in three doses at months 0, 1 and 6 to 898 subjects who were followed up for a median of over 800 days in parallel with 896 subjects in the placebo group
. Hepatitis E developed in 66 subjects in the placebo group versus 3 in the vaccine group, which translates into a 95.5% vaccine efficacy. Moreover, the increase by a factor of 10 in anti HEV IgG levels after the administration of the third dose of vaccine was evidence that the first two vaccine doses elicited a strong immune memory.
Another HEV vaccine based on the 50 kD recombinant capsid protein went through Phase III clinical trials at the Xiamen University in China  . The self-asssembled recombinant virus particle was analyzed at a 22-A resolution basis by cryo-electron microscopy and image reconstruction, yielding the first image of a T=1 particle with 30 morphological units showing protruding dimers at the icosahedral two-fold axes.
The combination of the HEV VLP vaccine with an inactivated HAV vaccine was studied in mice and showed that a dual HAV / HEV vaccination was feasible .
Plague is an exceptionally virulent, vector-borne zoonotic disease transmitted from rodents, especially rats, through the bites of infected fleas, most often the rat flea, Xenopsylla cheopsis. Many different species of mammals, including rats, squirrels, mice, prairie dogs and gerbils actually are animal reservoirs for the agent of plague, Yersinia pestis, which persists in the environment as the result of a stable and constant rodent-flea infection cycle, causing a fatal disease in murine and sciuride populations
. The reduction of rodent populations, whether as a consequence of the disease or of rodent control measures, compels fleas to seek new warm-blooded mammalian hosts, incidentally including humans.
The first major epidemic of plague to be historically recorded occurred in China in 224 BC. In Europe, plague was endemic in all of the Roman Empire, with severe outbreaks occurring occasionally, such as the outbreak which occurred in Rome in the third century AD, giving rise to one of the worst persecutions of Christians. Plague later came in long-lasting, dreaded pandemic waves  . The first documented pandemic, the Justinian plague, killed several million people in the Byzantine Empire during the 6th to 8th century. The second pandemic, the "Black Death", started in the middle of the 14th century and persisted over several hundred years, killing about 30% of the European population and culminating with the Great Plague of London in 1665. The third pandemic started in China in the middle of the 19th century and caused 10 million deaths in India alone.
Although the dramatic epidemics of urban plague have disappeared, due to improved sanitation and public health surveillance, plague still is a significant health problem in Africa, Asia and South America, which report around 2 000 cases every year with a global case fatality rate of 5% to 15%. The disease is endemic to Africa, India, and the southwestern states of the USA, and isolated outbreaks continue to this day in many regions of the world    . Africa, mainly The Democratic Republic of Congo and Madagascar, account for 96% of world cases since 1990. The identification of naturally occurring multiple-drug-resistant strains of Y pestis in Madagascar   , as well as the discovery of high frequency conjugative transfer of antibiotic resistance genes to Y pestis in the flea midgut  are matters of serious concern. Moreover, plague has attracted a considerable attention because of its possible use as an agent of biological warfare and terrorism .
Plague assumes three major clinical forms in humans: bubonic, pneumonic, and septicemic. Flea bites usually cause bubonic plague, whose name comes from the bubo, a painful swelling of the bite site-draining lymph nodes which often become hemorrhagic and necrotic (hence the name 'Black Death'). Without prompt antibiotic treatment, approximately 50% of bubonic cases rapidly progress to sepsis and death. About 30% of fleabites directly lead to sepsis, without prior evidence of a bubo  . Sepsis is characterized by circulatory collapse, coagulopathy, hemorrhage, respiratory distress, shock, and organ failure, leading to death in about 40% of cases. The most feared form is pneumonic plague because this form can readily be transmitted from person-to-person via inhalation of contaminated airborne droplets  . Symptoms begin with rigor, severe headache and malaise then quickly advance to fever, difficulty breathing, and cough that yields infectious, bright red sputum teeming with bacteria. The case fatality rate is close to 100% if no antibiotic treatment is given within the first 48 hours following symptoms onset  . The study of experimental Y pestis aerosols in animal models showed that 1µm particle aerosols resulted in both primary pneumonia and infection of the upper respiratory tract whereas 12 µm particles infection resulted in the attack of the nasal mucosa and nasal-associated lymphoid tissues (NALT) prior to bacteremic dissemination and secondary pneumonia .
The pathology of plague is very similar in rodents, nonhuman primates and humans    .
Yersinia pestis, first identified by Alexandre Yersin in 1894, is a Gram-negative, nonmotile bacterium that belongs to the family Enterobacteriacae. Three species in the genus Yersinia are pathogenic for humans: Y pestis, Y pseudotuberculosis and Y enterolytica, the latter two being the cause of self-limiting enteropathogenic infections characterized by diarrhoea, fever and abdominal pain. The extreme virulence of Y pestis mostly results from its virulence factors that impair the host innate immunity response, including phagocytosis, and allow the bacteria to multiply and spread unchecked in the host
The major mechanism that impairs the host phagocytosis response is a 70-kb plasmid (pCD1)-encoded Type III secretion system which is activated by growth of the bacterium at 37°C and whose function is to directly translocate Yersinia outer proteins (Yops) to neighboring host cells, mostly dendritic cells, macrophages and neutrophils, in which they disrupt signaling pathways, suppress cytokine production, debilitate the antibacterial defense mechanisms and promote apoptosis  . The pCD1 plasmid also carries the lcrV gene, which encodes the 37-kD low calcium response virulence antigen, LcrV-Ag, that serves as a positive regulator of the type III secretion system  . Y pestis lacking LcrV is avirulent in mouse models of plague disease. In addition, LcrV can activate Toll-like receptor 2 and trigger the release of IL-10   , a cytokine that suppresses innate immune functions  . LcrV also prevents the release of proinflammatory cytokines tumor necrosis factor (TNF)-? and y-interferon in murine and human macrophages .
Other Y pestis virulence factors include the F1 pilus antigen, a 17 kD polypeptide encoded by the caf gene that is carried on a large 100-kb plasmid (pMT1, or pFra). F1 is the major protein component of the outer capsule encompassing Y pestis bacilli and is believed to help avoid phagocytosis  . YopH, a protein tyrosine phosphatase that is part of the type III secretion system  , Pla, a plasminogen activator protease encoded by plasmid pPCP1, as well as murein (or Braun) lipoprotein (Lpp), which links the outer bacterial membrane to the peptidoglycan layer in Enterobacteriacae  are also virulence factors, as judged by the fact that their mutation or deletion attenuates the virulence of Y pestis in rodents, which is currently used as a basis for the development of live attenuated vaccine strains.
The first widely used plague vaccine was developed by Haffkine in 1897 using a heat-killed culture of Y pestis. The vaccine conferred significant protection against bubonic plague but induced severe adverse reactions including high fever in the majority of vaccinees. Moreover, later studies in rodents and nonhuman primates showed that the vaccine was unable to elicit protection against pneumonic plague. A formalin-killed whole-cell vaccine was developed in the mid-20th century in the USA and used to protect US military personnel against bubonic plague during the Vietnam War
, but it also caused severe adverse reactions and was unable to elicit protection against pneumonic plague. Its use was discontinued in 1999
The development of live attenuated plague vaccines began at the beginning of the 20th century using partially attenuated, pigmentation negative (pgm negative) Y pestis strains such as the Girard and Robic EV strain   and later derivatives  . Between 1934 and 1940, mass vaccination campaigns in Madagascar dramatically reduced the annual plague incidence (from 3500 to 200 cases). In spite of frequently reported side effects and residual virulence in nonhuman primates  , the live attenuated EV 76 and EV 88 strains are still in use in Russia and Central Asian republics today  , both for protecting humans and camels. Other live attenuated plague vaccines that are in early development include a DeltaYopH strain, which protected mice against high-dose parenteral or aerosol challenge after a single intranasal administration , a Deltalpp mutant  and a YadC mutant 123] , as well as an IpxM mutant of the already partially attenuated EV strain of Y pestis  . In addition, the use of Yersinia pseudotuberculosis as a Jennerian vaccine against plague has been entertained because it shares high genetic identity with Y pestis, is less virulent and can be administered by the oral route .
The development of subunit plague vaccines started in the 1950s, focusing on the use of the capsular F1 (Caf1) pilus antigen. Vaccination with F1 protected rats, mice and nonhuman primates against subcutaneous and aerosol challenge with virulent Y pestis    . However, Y pestis variants lacking caf1 were found which not only were fully virulent in animal models of bubonic and pneumonic plague, but also broke through the immune responses generated with F1 subunit vaccines   .
Unlike F1, the Lcr V antigen was found to be critical for Y pestis virulence    and, when used as a subunit vaccine, generated high titers of antibodies that conferred protective immunity against bubonic and pneumonic plague in mice, guinea pigs and nonhuman primates, whether the strain used for challenge was F1 positive or not     . Passive immunization with an anti-Lcr V monoclonal antibody was shown to protect mice against aerolized Y pestis, even when administered 48 h postinfection  . Finally, anti-Lcr V antibodies were demonstrated to neutralize Y pestis-mediated macrophage cytotoxicity in a dose-dependent manner, which could be used as an in vitro assay as a correlate of protective immunity  . In view of the immune modulatory properties of Lcr V, concerns were raised regarding its safety as a vaccine in humans. A truncated version of the Lcr V antigen, V10, which lacks amino acids 271 to 300, was developed that showed reduced immune modulatory properties while offering full protection of mice against bubonic and pneumonic plague    and could be used advantageously in place of the full molecule.
Candidate vaccines containing either a combination of F1 and Lcr V antigens or a recombinant F1-Lcr V fusion protein in alum or alhydrogel formulations have been developed that efficiently protect mice against pulmonary Y pestis challenge       and elicit long-lasting protective antibodies able to neutralize Y pestis-mediated cytotoxicity of macrophages in cynomolgus macaques  . The F1-V vaccine also protected black-footed ferrets against oral challenge with Y pestis  . Both vaccines appeared to be safe and immunogenic in human trials   . A spray-freeze-dried F1-V fusion protein powder vaccine was recently developed that could be administered either by the IM or the ID route with similar protective efficacy in mice. The vaccine could also be administered by the intranasal route but an extra dose was required to achieve the same level of protection  . The DynPort Vaccine Company (DVC) is managing the advanced development of a rF1-V vaccine for the US Department of Defense (DOD) .
The possibility of developing a dual vaccine against anthrax and plague was investigated in a murine model by combining equal amounts of the anthrax rPA antigen and the Y pestis F1-V antigen. The vaccine was able to elicit a robust IgG and IgG1 response in mice against both antigens when administered by the SC route and a robust IgG2 response when administered by the intranasal route with appropriate adjuvants. Circulating antibody levels were still detectable at 6 months post primary immunization .
The US Army Medical Research Institute of Infectious Diseases (USAMRIID) demonstrated however that while the F1/V vaccines efficiently protected cynomolgus macaques against aerosolized Y pestis challenge, they failed to do so in African green monkeys, which raises the question of their eventual efficacy in humans  . A number of approaches are underway to increase the efficacy of the subunit F1/V vaccines  , such as the introduction of point mutations in the V antigen  or the use of other adjuvant formulations than alhydrogel. Thus, the use of flagellin as an adjuvant was tested by generating a flagellin-F1-V triple fusion protein that elicited robust antigen-specific humoral immunity in mice and two species of nonhuman primates and fully protected mice against intranasal Y pestis challenge  . The flagellin-F1-V antigen showed remarkable stability at temperatures between 4° and 25°C. In another approach, a promising intranasal vaccine against pneumonic plague was developed using lipid A mimetics as adjuvants, which showed high protective efficacy in both mice and rats  . In still another approach, rF1 and V antigens were separately microencapsulated in polymeric microspheres, mixed together and used to immunize mice by either the IM or intranasal route, resulting in high levels of serum IgGs, secretion of cytokines by the spleen and draining lymph nodes and protection against high level Y pestis challenge after a single immunization .
Protective efficacy of DNA vaccines was studied using plasmids that encoded the F1 and V antigens together with interleukin 12 (IL-12) as an adjuvant. DNA vaccines were administered either by the intranasal or the IM route, but protection was reached only after three weekly doses followed by protein boosts  .
Improving the efficacy of F1- and/or Lcr V-based vaccines by delivering the antigens via live attenuated recombinant vectors was also attempted using attenuated Salmonella enteritica serovar Typhimurium (Salomonella typhimurium) as a vector      . A single oral dose of a Samonella-F1-antigen recombinant protected mice against bubonic plague challenge, but not against pneumonic plague challenge. Protection against pneumonic plague challenge required the dual expression of both the F1 and the V antigen by the Salmonella vector  . The use of a vesicular stomatitis virus (VSV) vector expressing the V antigen and administered in a prime-boost regimen also protected mice against intranasal challenge with Y pestis  . The same protective efficacy was obtained with a single-dose IM immunization with an adenovirus recombinant expressing the V antigen .
Mice immunized by SC immunization with F1-V antigen purified from Nicotiana tabacum leaves expressing the F1-V fusion antigen in chloroplasts were boosted by oral delivery of the transgenic plants, which induced effective protection against aerosolized Y pestis challenge .
In spite of all these efforts, and the wealth of investigational approaches, we still currently lack a safe, effective and licensed vaccine for pneumonic plague, which is nearly always fatal and can be intentionally transmitted by weaponized strains of Y pestis. None of the live attenuated or live recombinant plague vaccine candidates is ready yet for an application for a license, which will have to be in accordance with the FDA 'Animal Rule' that requires safety and immunogenicity data in humans along with robust efficacy data in more than one animal model.
Rabies is a viral encephalitis transmitted from animal to animal and from animal to man through saliva. Animal bites introduce the virus into muscle and nerve ending-rich tissues from which it penetrates into nerve cells where it replicates and progressively travels through the spinal cord to the brain. This process usually requires weeks or even months, depending upon the distance from the bite site to the brain. Replication of the virus in the brain causes hydrophobia, hallucinations, aggressive behavior, and paralysis, eventually leading to coma and death. The virus also spreads to salivary glands and the skin, cornea, nasal and intestinal mucosa and other organs including kidneys. The disease thrived from most ancient times (its first written description can be found in the Babylon Codex, 23 centuries BC) to the end of the 19th century when, in 1885, Louis Pasteur and collaborators succeeded in the first cure of human rabies through post-exposure vaccination
. More than 120 years later, however, the disease still continues to affect mankind, especially in developing countries in Africa, in South and South-East Asia, and to a lesser extent Latin America.
In nature, rabies is a disease of wild carnivores, involving dogs, cats, wolves, foxes, coyotes, jackals, raccoons, skunks and also bats as reservoirs and vectors. All mammalian species are believed to be susceptible, including nonhuman primates. Human infection almost always results from the bite of an infected animal, although transmission of the virus through transplantation of infected corneas and other organs (heart, liver and kidney) has been reported. On rare occasions, the virus was also reported to be transmitted by aerosols in caves populated by rabies-infected bats. According to WHO, more than 3.3 billion people are at risk for rabies in over 85 countries worldwide   . About 55 000 deaths from rabies are estimated to occur every year, 99% of which are the consequence of dog bites   . Of these 55 000 deaths, 31 000 are estimated to occur in Asia (20 000 in India alone) and 24 000 in Africa. The annual incidence of animal bites in many countries can be as high as 100-200 bites per 100 000 population. In 2005, more than 12 million individuals received a post-exposure prophylaxis (PEP) treatment against rabies, preventing an estimated 280 000 deaths .
Canine rabies is still widespread in stray dogs in Asia, Africa and parts of Latin America. Control of rabies in these countries is often hampered by religious beliefs and cultural habits. For example, Buddhist and Hindu ethics restrain culling of the canine population. India and Thailand have prohibited the euthanasia of stray dogs by municipalities. In these countries, stray dogs account for >90% of human rabies exposures, especially among 5-14 years old children in rural or peri-urban areas. Human rabies has been endemic in India for immemorial times, but the actual incidence of the disease never had been carefully studied. A recent survey on 10.8 million persons in mainland India led to conclude that the annual incidence of rabies was 2 per 100 000 population  . In most developing countries, however, the true incidence of rabies is largely underestimated, due to poor reporting.
In countries where an effective rabies control has been implemented, various wildlife species including bats have become the main reservoir of rabies and most human cases are secondary to bites by rabid bats   . In the USA, the predominant vectors for rabies are skunks in the western and central states, raccoons in the eastern states, coyotes in the far south and foxes at the Canadian border and in Alaska. In Western Europe, prior to the implementation of wildlife vaccination, 83% of rabid animals were foxes. Most of Western Europe is now rabies-free, and several countries in Central and Eastern Europe are almost rabies-free, but rabies is still a problem in the Baltic countries, Ukraine, Russia and Independent States of former USSR.
Rabies virus is an enveloped, bullet-shaped virus which belongs to the genus Lyssavirus in the family Rhabdoviridae. The negative sense viral RNA genome encodes five viral proteins, the N (nucleocapsid), P, M (membrane), G (envelope glycoprotein) and L (replicase) proteins. Seven virus genotypes have been described, genotype 1 corresponding to the rabies virus and genotypes 2 to 7 to bat lyssaviruses. These are: genotype 2 (Lagos bat virus), genotype 3 (Central Africa Mokola virus), genotype 4 (South Africa Duvenhage virus), genotypes 5 and 6 (European bat lyssaviruses) and genotype 7 (Australian bat virus). New Lyssaviruses have been identified (e.g. central Asia) and the addition of new genotypes is under consideration. All these viruses can be pathogenic for humans.
The G protein, which forms spikes at the surface of the virion, is responsible for the attachment of the virus to virus receptors and bears the neutralization epitopes. There seems to be little cross neutralization between genotype 1 (rabies virus) and genotypes 2 (Lagos bat virus) and 3 (Mokola virus).
For more than 70 years after Pasteur's original work, inactivated vaccines were produced from sheep, goat or rabbit brains and contained nerve tissue, a cause of severe neurological adverse events. The Semple vaccine, which was produced on sheep or goat brains and inactivated with phenol was until recently commonly used in humans in many countries in Africa and Asia. The first rabies vaccine produced in animal tissues with low myelin content was prepared in the 1960s by Fuenzalida and colleagues
starting from infected suckling mouse brains, again using phenol as the inactivating agent. Suckling mouse brain vaccines (SMBV) were the most frequently used vaccines for many years, until their production started being discontinued a few years ago, especially in major SMBV producing countries such as Brazil and Mexico, to be replaced by a number of inactivated rabies vaccines produced on either primary or continuous cell lines or embryonated eggs.
The first modern rabies vaccine (Human diploid cell vaccine, HDCV) was developed at the Wistar Institute in Philadelphia by propagating the rabies virus on the human diploid cell line WI-38 and using beta-propiolactone for its inactivation  . This was followed by a purified vaccine produced in Vero cell cultures (PVRV), and also inactivated by beta-propiolactone, which was developed by Sanofi Pasteur   ; and a purified vaccine produced on primary chick embryo cells (PCECV), developed by Novartis. The three vaccines show comparable tolerance and immunogenicity and their efficacy was demonstrated in several PEP clinical trials. In addition, a primary baby hamster kidney cell culture vaccine (PHKCV), a purified duck embryo vaccine (PDEV), three Vero cell-based vaccines and one HDCV have been developed in China and India.
These vaccines can be used either for preventive immunization or for PEP. Preventive immunization is recommended for certain professional groups such as veterinarians and for travelers to rabies-endemic countries. There is no doubt that preventive vaccination of children in areas where rabies is endemic should also be given thorough consideration. The recommended preventive immunization regimen consists in three IM doses at 0, 7, and 21 or 28 days. The longevity of rabies neutralizing antibody anamnestic response in vaccinated persons was examined on 118 Thai volunteers who had received a cell culture vaccine 5 to 20 years previously and who each received a booster ID injection of 0.1 mL PVRV. All volunteers except one had detectable neutralizing antibody titers on day 0 and responded to the ID booster immunization with an accelerated antibody response, indicative of a long-lasting immune memory conferred by the vaccine .
Rabies vaccines are mostly used for PEP after bites from suspect rabid animals, as the time the virus takes to travel to the brain can be up to 2 months, which allows the immune system to mount an immune barrier in response to PEP before symptoms occur. The recommended schedule for PEP is five doses at 0, 3, 7, 14 and 28 days, often coupled to passive immunization with rabies immunoglobulins (RIGs). Two types of RIG are currently available, human IgGs (HRIGs) and highly purified equine IgGs (ERIGs). The overall shortage of RIGs and their current cost however represent a real public health threat in many countries. The use of rabies monoclonal antibodies (MRIGs) to replace RIG in PEP has been studied by various groups  and one such cocktail of two human monoclonals was recently tested in a Phase I study .
The relatively high cost of a full PEP regimen using IM immunizations also prompted attempts at using a reduced dose of vaccine for PEP, replacing IM by ID inoculations and using 0.1 mL (1/5th of a dose) of vaccine   . Various ID post-exposure regimens (PEP) have undergone extensive evaluation, especially by the Thai Red Cross (TRC) in Thailand, using two ID injections on days 0, 3 and 7 followed by two injections day 28    . The immunogenicity, tolerance and efficacy of PEP using either PCECV or PVRV administered ID at 0.1 mL per site according to the WHO recommended protocols  have been well documented    . Post-exposure ID vaccination is also routinely practiced in India, the Philippines and Sri Lanka, where it reduced the cost of PEP intervention by about 80%  .
The possibility of using the ID route of immunization for rabies pre-exposure vaccination was eventually tested in a randomized, open-label Phase II trial in schoolchildren in Thailand using 1/5th of a dose of purified chick embryo cell vaccine (PCECV) on days 0, 7, and 28 or 0, 7 and 21: 100% of the children developed protective rabies-neutralizing antibody titers   . An abbreviated pre-exposure vaccination schedule using two ID injections at two sites on day 0 was found to lead to persistence of neutralizing antibodies one year later  . The possibility of routinely immunizing children in rabies-endemic countries using a simplified ID vaccination regimen is being explored in Thailand, again showing that a two-site ID immunization done on the same day using 0.1 mL of vaccine in each site could prime the human host immune memory for at least one to three years  .
It should be realized, however, that there will not be any easy solution to the problem of rabies in rabies-endemic countries if no attempt is made at eliminating the virus from its animal reservoirs. Vaccinating dogs against rabies has already been demonstrated as a highly efficacious preventive measure   . Similarly, oral vaccination of foxes and other wildlife using either live attenuated rabies virus mutants or a live vaccinia virus recombinant that expressed the rabies G glycoprotein (RaboralTM) was highly successful at eliminating rabies from Western Europe. Different strategies, kinds and shapes of baits have been developed for targeting the major wild rabies reservoirs: stray dogs, foxes, coyotes and raccoon dogs    .
No disease exceeds the case fatality rate of rabies. Progress must continue towards the elimination of human rabies, itself depending on wildlife rabies control and canine rabies elimination  . The declaration of an Annual World Rabies Day, September 8, should hopefully raise public awareness of the severity of the disease .
 Gao F, Bailes E, Robertson DL, Chen Y, Rodenburg CM, Michael SF, et al. Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 1999;397:436-41.
 Korber B, Muldoon M, Theiler J, Gao F, Gupta R, Lapedes A, et al. Timing the ancestor of the HIV-1 pandemic strains. Science 2000;288:1789-96.
 Brachman PS, Friedlander AM, Grabenstein JD. Anthrax vaccines. In: Plotkin SA, Orenstein WA, Offit P, editors. Vaccine 5th ed. Philadelphia: Saunders, Elsevier, 2008: 111-27.
 Dixon TC, Meselson M, Guillemin J, Hanna PC. Anthrax. N Engl J Med 1999;341:815-26.
 Schwartz RS. Racial profiling in medical research. N Engl J Med 2001;344:1392-3.
 Holty JE, Bravata DM, Liu H, Olshen RA, McDonald KM, Owens DK. Systematic review: a century of inhalational anthrax cases from 1900 to 2005. Ann Intern Med 2006;144:270-80.
 Update: Investigation of bioterrorism-related anthrax, 2001. MMWR Morb Mortal Wkly Rep 2001;50:1008-10.
 Wallin A, Luksiene Z, Zagminas K, Surkiene G. Public health and bioterrorism: renewed threat of anthrax and smallpox. Medicina (Kaunas) 2007;43:278-84.
 Fasanella A, Palazzo L, Petrella A, Quaranta V, Romanelli B, Garofolo G. Anthrax in red deer (Cervus elaphus), Italy. Emerg Infect Dis 2007;13:1118-9.
 Collier RJ, Young JA. Anthrax toxin. Annu Rev Cell Dev Biol 2003;19:45-70.
 Duesbery NS, Webb CP, Leppla SH, Gordon VM, Klimpel KR, Copeland TD, et al. Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science 1998;280:734-7.
 Leppla SH. Anthrax toxin edema factor: a bacterial adenylate cyclase that increases cyclic AMP concentrations of eukaryotic cells. Proc Natl Acad Sci U S A 1982;79:3162-6.
 Gupta M, Alam S, Bhatnagar R. Catalytically inactive anthrax toxin(s) are potential prophylactic agents. Vaccine 2007;25:8410-9.
 Sterne M. Distribution and economic importance of anthrax. Fed Proc 1967;26:1493-5.
 Green BD, Battisti L, Koehler TM, Thorne CB, Ivins BE. Demonstration of a capsule plasmid in Bacillus anthracis. Infect Immun 1985;49:291-7.
 Ivins BE, Ezzell JW, Jr., Jemski J, Hedlund KW, Ristroph JD, Leppla SH. Immunization studies with attenuated strains of Bacillus anthracis. Infect Immun 1986;52:454-8.
 Passalacqua KD, Bergman NH. Bacillus anthracis: interactions with the host and establishment of inhalational anthrax. Future Microbiol 2006;1:397-415.
 World Health Organ ( WHO). WHO guidelines on Anthrax in human and animals. Geneva; 2008.
 Turnbull PC. Anthrax vaccines: past, present and future. Vaccine 1991;9:533-9.
 Brey RN. Molecular basis for improved anthrax vaccines. Adv Drug Deliv Rev 2005;57:1266-92.
 Pittman PR, Hack D, Mangiafico J, Gibbs P, McKee KT, Jr., Friedlander AM, et al. Antibody response to a delayed booster dose of anthrax vaccine and botulinum toxoid. Vaccine 2002;20:2107-15.
 Pittman PR, Kim-Ahn G, Pifat DY, Coonan K, Gibbs P, Little S, et al. Anthrax vaccine: immunogenicity and safety of a dose-reduction, route-change comparison study in humans. Vaccine 2002;20:1412-20.
 Marano N, Plikaytis BD, Martin SW, Rose C, Semenova VA, Martin SK, et al. Effects of a reduced dose schedule and intramuscular administration of anthrax vaccine adsorbed on immunogenicity and safety at 7 months: a randomized trial. JAMA 2008;300:1532-43.
 Fellows PF, Linscott MK, Ivins BE, Pitt ML, Rossi CA, Gibbs PH, et al. Efficacy of a human anthrax vaccine in guinea pigs, rabbits, and rhesus macaques against challenge by Bacillus anthracis isolates of diverse geographical origin. Vaccine 2001;19:3241-7.
 Baillie L. The development of new vaccines against Bacillus anthracis. J Appl Microbiol 2001;91:609-13.
 Goodman L. Taking the sting out of the anthrax vaccine. J Clin Invest 2004;114:868-9.
 Phipps AJ, Premanandan C, Barnewall RE, Lairmore MD. Rabbit and nonhuman primate models of toxin-targeting human anthrax vaccines. Microbiol Mol Biol Rev 2004;68:617-29.
 Tournier JN, Ulrich RG, Quesnel-Hellmann A, Mohamadzadeh M, Stiles BG. Anthrax, toxins and vaccines: a 125-year journey targeting Bacillus anthracis. Expert Rev Anti Infect Ther 2009;7:219-36.
 Makino S, Uchida I, Terakado N, Sasakawa C, Yoshikawa M. Molecular characterization and protein analysis of the cap region, which is essential for encapsulation in Bacillus anthracis. J Bacteriol 1989;171:722-30.
 Little SF, Ivins BE, Fellows PF, Friedlander AM. Passive protection by polyclonal antibodies against Bacillus anthracis infection in guinea pigs. Infect Immun 1997;65:5171-5.
 Ivins BE, Pitt ML, Fellows PF, Farchaus JW, Benner GE, Waag DM, et al. Comparative efficacy of experimental anthrax vaccine candidates against inhalation anthrax in rhesus macaques. Vaccine 1998;16:1141-8.
 Scorpio A, Blank TE, Day WA, Chabot DJ. Anthrax vaccines: Pasteur to the present. Cell Mol Life Sci 2006;63:2237-48.
 Wimer-Mackin S, Hinchcliffe M, Petrie CR, Warwood SJ, Tino WT, Williams MS, et al. An intranasal vaccine targeting both the Bacillus anthracis toxin and bacterium provides protection against aerosol spore challenge in rabbits. Vaccine 2006;24:3953-63.
 Campbell JD, Clement KH, Wasserman SS, Donegan S, Chrisley L, Kotloff KL. Safety, reactogenicity and immunogenicity of a recombinant protective antigen anthrax vaccine given to healthy adults. Hum Vaccin 2007;3:205-11.
 Boyaka PN, Tafaro A, Fischer R, Leppla SH, Fujihashi K, McGhee JR. Effective mucosal immunity to anthrax: neutralizing antibodies and Th cell responses following nasal immunization with protective antigen. J Immunol 2003;170:5636-43.
 Gaur R, Gupta PK, Banerjea AC, Singh Y. Effect of nasal immunization with protective antigen of Bacillus anthracis on protective immune response against anthrax toxin. Vaccine 2002;20:2836-9.
 Bielinska AU, Janczak KW, Landers JJ, Makidon P, Sower LE, Peterson JW, et al. Mucosal immunization with a novel nanoemulsion-based recombinant anthrax protective antigen vaccine protects against Bacillus anthracis spore challenge. Infect Immun 2007;75:4020-9.
 Yin Y, Zhang J, Dong D, Liu S, Guo Q, Song X, et al. Chimeric hepatitis B virus core particles carrying an epitope of anthrax protective antigen induce protective immunity against Bacillus anthracis. Vaccine 2008;26:5814-21.
 Bandurska K, Brodzik R, Spitsin S, Kohl T, Portocarrero C, Smirnov Y, et al. Plant-produced hepatitis B core protein chimera carrying anthrax protective antigen domain-4. Hybridoma (Larchmt) 2008;27:241-7.
 Gauthier YP, Tournier JN, Paucod JC, Corre JP, Mock M, Goossens PL, et al. Efficacy of a vaccine based on protective antigen and killed spores against experimental inhalational anthrax. Infect Immun 2009;77:1197-207.
 Sloat BR, Shaker DS, Le UM, Cui Z. Nasal immunization with the mixture of PA63, LF, and a PGA conjugate induced strong antibody responses against all three antigens. FEMS Immunol Med Microbiol 2008;52:169-79.
 Fasanella A, Tonello F, Garofolo G, Muraro L, Carattoli A, Adone R, et al. Protective activity and immunogenicity of two recombinant anthrax vaccines for veterinary use. Vaccine 2008;26:5684-8.
 Jameel S. Molecular biology and pathogenesis of hepatitis E virus. Expert Rev Mol Med 1999;1999:1-16.
 Labrique AB, Thomas DL, Stoszek SK, Nelson KE. Hepatitis E: an emerging infectious disease. Epidemiol Rev 1999;21:162-79.
 Acharya SK, Panda SK. Hepatitis E virus: epidemiology, diagnosis, pathology and prevention. Trop Gastroenterol 2006;27:63-8.
 Panda SK, Thakral D, Rehman S. Hepatitis E virus. Rev Med Virol 2007;17:151-80.
 Chandra V, Taneja S, Kalia M, Jameel S. Molecular biology and pathogenesis of hepatitis E virus. J Biosci 2008;33:451-64.
 Worm HC, Wirnsberger G. Hepatitis E vaccines: progress and prospects. Drugs 2004;64:1517-31.
 Khuroo MS, Kamili S, Yattoo GN. Hepatitis E virus infection may be transmitted through blood transfusions in an endemic area. J Gastroenterol Hepatol 2004;19:778-84.
 Mast EE, Kuramoto IK, Favorov MO, Schoening VR, Burkholder BT, Shapiro CN, et al. Prevalence of and risk factors for antibody to hepatitis E virus seroreactivity among blood donors in Northern California. J Infect Dis 1997;176:34-40.
 Thomas DL, Yarbough PO, Vlahov D, Tsarev SA, Nelson KE, Saah AJ, et al. Seroreactivity to hepatitis E virus in areas where the disease is not endemic. J Clin Microbiol 1997;35:1244-7.
 Mansuy JM, Legrand-Abravanel F, Calot JP, Peron JM, Alric L, Agudo S, et al. High prevalence of anti-hepatitis E virus antibodies in blood donors from South West France. J Med Virol 2008;80:289-93.
 van der Poel WH, Verschoor F, van der Heide R, Herrera MI, Vivo A, Kooreman M, et al. Hepatitis E virus sequences in swine related to sequences in humans, The Netherlands. Emerg Infect Dis 2001;7:970-6.
 Huang FF, Haqshenas G, Guenette DK, Halbur PG, Schommer SK, Pierson FW, et al. Detection by reverse transcription-PCR and genetic characterization of field isolates of swine hepatitis E virus from pigs in different geographic regions of the United States. J Clin Microbiol 2002;40:1326-32.
 Pei Y, Yoo D. Genetic characterization and sequence heterogeneity of a canadian isolate of Swine hepatitis E virus. J Clin Microbiol 2002;40:4021-9.
 Tei S, Kitajima N, Takahashi K, Mishiro S. Zoonotic transmission of hepatitis E virus from deer to human beings. Lancet 2003;362:371-3.
 Takahashi K, Kitajima N, Abe N, Mishiro S. Complete or near-complete nucleotide sequences of hepatitis E virus genome recovered from a wild boar, a deer, and four patients who ate the deer. Virology 2004;330:501-5.
 Huang FF, Sun ZF, Emerson SU, Purcell RH, Shivaprasad HL, Pierson FW, et al. Determination and analysis of the complete genomic sequence of avian hepatitis E virus (avian HEV) and attempts to infect rhesus monkeys with avian HEV. J Gen Virol 2004;85:1609-18.
 Tei S, Kitajima N, Ohara S, Inoue Y, Miki M, Yamatani T, et al. Consumption of uncooked deer meat as a risk factor for hepatitis E virus infection: an age- and sex-matched case-control study. J Med Virol 2004;74:67-70.
 Matsuda H, Okada K, Takahashi K, Mishiro S. Severe hepatitis E virus infection after ingestion of uncooked liver from a wild boar. J Infect Dis 2003;188:944.
 Zheng Y, Ge S, Zhang J, Guo Q, Ng MH, Wang F, et al. Swine as a principal reservoir of hepatitis E virus that infects humans in eastern China. J Infect Dis 2006;193:1643-9.
 Feagins AR, Opriessnig T, Guenette DK, Halbur PG, Meng XJ. Detection and characterization of infectious Hepatitis E virus from commercial pig livers sold in local grocery stores in the USA. J Gen Virol 2007;88:912-7.
 Kamar N, Selves J, Mansuy JM, Ouezzani L, Peron JM, Guitard J, et al. Hepatitis E virus and chronic hepatitis in organ-transplant recipients. N Engl J Med 2008;358:811-7.
 Hamid SS, Atiq M, Shehzad F, Yasmeen A, Nissa T, Salam A, et al. Hepatitis E virus superinfection in patients with chronic liver disease. Hepatology 2002;36:474-8.
 Emerson SU, Purcell RH. Hepatitis E virus. Rev Med Virol 2003;13:145-54.
 Patra S, Kumar A, Trivedi SS, Puri M, Sarin SK. Maternal and fetal outcomes in pregnant women with acute hepatitis E virus infection. Ann Intern Med 2007;147:28-33.
 Khuroo MS, Teli MR, Skidmore S, Sofi MA, Khuroo MI. Incidence and severity of viral hepatitis in pregnancy. Am J Med 1981;70:252-5.
 Balayan MS. Epidemiology of hepatitis E virus infection. J Viral Hepat 1997;4:155-65.
 Prusty BK, Hedau S, Singh A, Kar P, Das BC. Selective suppression of NF-kBp65 in hepatitis virus-infected pregnant women manifesting severe liver damage and high mortality. Mol Med 2007;13:518-26.
 Reyes GR, Purdy MA, Kim JP, Luk KC, Young LM, Fry KE, et al. Isolation of a cDNA from the virus responsible for enterically transmitted non-A, non-B hepatitis. Science 1990;247:1335-9.
 Reyes GR, Huang CC, Tam AW, Purdy MA. Molecular organization and replication of hepatitis E virus (HEV). Arch Virol Suppl 1993;7:15-25.
 Arankalle VA, Paranjape S, Emerson SU, Purcell RH, Walimbe AM. Phylogenetic analysis of hepatitis E virus isolates from India (1976-1993). J Gen Virol 1999;80 ( Pt 7):1691-700.
 Graff J, Zhou YH, Torian U, Nguyen H, St Claire M, Yu C, et al. Mutations within potential glycosylation sites in the capsid protein of hepatitis E virus prevent the formation of infectious virus particles. J Virol 2008;82:1185-94.
 Emerson SU, Zhang M, Meng XJ, Nguyen H, St Claire M, Govindarajan S, et al. Recombinant hepatitis E virus genomes infectious for primates: importance of capping and discovery of a cis-reactive element. Proc Natl Acad Sci U S A 2001;98:15270-5.
 Emerson SU, Nguyen H, Graff J, Stephany DA, Brockington A, Purcell RH. In vitro replication of hepatitis E virus (HEV) genomes and of an HEV replicon expressing green fluorescent protein. J Virol 2004;78:4838-46.
 Tanaka T, Takahashi M, Kusano E, Okamoto H. Development and evaluation of an efficient cell-culture system for Hepatitis E virus. J Gen Virol 2007;88:903-11.
 Takahashi M, Tanaka T, Azuma M, Kusano E, Aikawa T, Shibayama T, et al. Prolonged fecal shedding of hepatitis E virus (HEV) during sporadic acute hepatitis E: evaluation of infectivity of HEV in fecal specimens in a cell culture system. J Clin Microbiol 2007;45:3671-9.
 Robinson RA, Burgess WH, Emerson SU, Leibowitz RS, Sosnovtseva SA, Tsarev S, et al. Structural characterization of recombinant hepatitis E virus ORF2 proteins in baculovirus-infected insect cells. Protein Expr Purif 1998;12:75-84.
 Tsarev SA, Tsareva TS, Emerson SU, Govindarajan S, Shapiro M, Gerin JL, et al. Successful passive and active immunization of cynomolgus monkeys against hepatitis E. Proc Natl Acad Sci U S A 1994;91:10198-202.
 Tsarev SA, Tsareva TS, Emerson SU, Govindarajan S, Shapiro M, Gerin JL, et al. Recombinant vaccine against hepatitis E: dose response and protection against heterologous challenge. Vaccine 1997;15:1834-8.
 Clayson ET, Shrestha MP, Vaughn DW, Snitbhan R, Shrestha KB, Longer CF, et al. Rates of hepatitis E virus infection and disease among adolescents and adults in Kathmandu, Nepal. J Infect Dis 1997;176:763-6.
 Shrestha MP, Scott RM, Joshi DM, Mammen MP, Jr., Thapa GB, Thapa N, et al. Safety and efficacy of a recombinant hepatitis E vaccine. N Engl J Med 2007;356:895-903.
 Xing L, Kato K, Li T, Takeda N, Miyamura T, Hammar L, et al. Recombinant hepatitis E capsid protein self-assembles into a dual-domain T = 1 particle presenting native virus epitopes. Virology 1999;265:35-45.
 Dong C, Dai X, Meng JH. The first experimental study on a candidate combined vaccine against hepatitis A and hepatitis E. Vaccine 2007;25:1662-8.
 Perry RD, Fetherston JD. Yersinia pestis--etiologic agent of plague. Clin Microbiol Rev 1997;10:35-66.
 Williamson ED, Simpson AJ, Titball RW. Plague Vaccines. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines 5th ed. Philadelphia: Saunders,Elsevier, 2008: 519-29.
 Mudur G. India's pneumonic plague outbreak continues to baffle. BMJ 1995;311:706.
 Bertherat E, Lamine KM, Formenty P, Thuier P, Mondonge V, Mitifu A, et al. [Major pulmonary plague outbreak in a mining camp in the Democratic Republic of Congo: brutal awakening of an old scourge]. Med Trop (Mars) 2005;65:511-4.
 Prentice MB, Rahalison L. Plague. Lancet 2007;369:1196-207.
 Galimand M, Guiyoule A, Gerbaud G, Rasoamanana B, Chanteau S, Carniel E, et al. Multidrug resistance in Yersinia pestis mediated by a transferable plasmid. N Engl J Med 1997;337:677-80.
 Guiyoule A, Gerbaud G, Buchrieser C, Galimand M, Rahalison L, Chanteau S, et al. Transferable plasmid-mediated resistance to streptomycin in a clinical isolate of Yersinia pestis. Emerg Infect Dis 2001;7:43-8.
 Hinnebusch BJ, Rosso ML, Schwan TG, Carniel E. High-frequency conjugative transfer of antibiotic resistance genes to Yersinia pestis in the flea midgut. Mol Microbiol 2002;46:349-54.
 Inglesby TV, Dennis DT, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, et al. Plague as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA 2000;283:2281-90.
 Sebbane F, Jarrett CO, Gardner D, Long D, Hinnebusch BJ. Role of the Yersinia pestis plasminogen activator in the incidence of distinct septicemic and bubonic forms of flea-borne plague. Proc Natl Acad Sci U S A 2006;103:5526-30.
 Kool JL. Risk of person-to-person transmission of pneumonic plague. Clin Infect Dis 2005;40:1166-72.
 Koirala J. Plague: disease, management, and recognition of act of terrorism. Infect Dis Clin North Am 2006;20:273-87.
 Thomas RJ, Webber D, Collinge A, Stagg AJ, Bailey SC, Nunez A, et al. Different pathologies but equal levels of responsiveness to the recombinant F1 and V antigen vaccine and ciprofloxacin in a murine model of plague caused by small- and large-particle aerosols. Infect Immun 2009;77:1315-23.
 Sebbane F, Gardner D, Long D, Gowen BB, Hinnebusch BJ. Kinetics of disease progression and host response in a rat model of bubonic plague. Am J Pathol 2005;166:1427-39.
 Lathem WW, Crosby SD, Miller VL, Goldman WE. Progression of primary pneumonic plague: a mouse model of infection, pathology, and bacterial transcriptional activity. Proc Natl Acad Sci U S A 2005;102:17786-91.
 Bubeck SS, Cantwell AM, Dube PH. Delayed inflammatory response to primary pneumonic plague occurs in both outbred and inbred mice. Infect Immun 2007;75:697-705.
 Smiley ST. Current challenges in the development of vaccines for pneumonic plague. Expert Rev Vaccines 2008;7:209-21.
 Cornelis GR. Yersinia type III secretion: send in the effectors. J Cell Biol 2002;158:401-8.
 Brubaker RR. Interleukin-10 and inhibition of innate immunity to Yersiniae: roles of Yops and LcrV (V antigen). Infect Immun 2003;71:3673-81.
 Viboud GI, Bliska JB. Yersinia outer proteins: role in modulation of host cell signaling responses and pathogenesis. Annu Rev Microbiol 2005;59:69-89.
 Heesemann J, Sing A, Trulzsch K. Yersinia's stratagem: targeting innate and adaptive immune defense. Curr Opin Microbiol 2006;9:55-61.
 Marketon MM, DePaolo RW, DeBord KL, Jabri B, Schneewind O. Plague bacteria target immune cells during infection. Science 2005;309:1739-41.
 Price SB, Cowan C, Perry RD, Straley SC. The Yersinia pestis V antigen is a regulatory protein necessary for Ca2(+)-dependent growth and maximal expression of low-Ca2+ response virulence genes. J Bacteriol 1991;173:2649-57.
 Nakajima R, Motin VL, Brubaker RR. Suppression of cytokines in mice by protein A-V antigen fusion peptide and restoration of synthesis by active immunization. Infect Immun 1995;63:3021-9.
 Sing A, Rost D, Tvardovskaia N, Roggenkamp A, Wiedemann A, Kirschning CJ, et al. Yersinia V-antigen exploits toll-like receptor 2 and CD14 for interleukin 10-mediated immunosuppression. J Exp Med 2002;196:1017-24.
 Redpath S, Ghazal P, Gascoigne NR. Hijacking and exploitation of IL-10 by intracellular pathogens. Trends Microbiol 2001;9:86-92.
 Nakajima R, Brubaker RR. Association between virulence of Yersinia pestis and suppression of gamma interferon and tumor necrosis factor alpha. Infect Immun 1993;61:23-31.
 Sebbane F, Jarrett C, Gardner D, Long D, Hinnebusch BJ. The Yersinia pestis caf1M1A1 fimbrial capsule operon promotes transmission by flea bite in a mouse model of bubonic plague. Infect Immun 2009;77:1222-9.
 Bubeck SS, Dube PH. Yersinia pestis CO92 delta yopH is a potent live, attenuated plague vaccine. Clin Vaccine Immunol 2007;14:1235-8.
 Sha J, Agar SL, Baze WB, Olano JP, Fadl AA, Erova TE, et al. Braun lipoprotein (Lpp) contributes to virulence of yersiniae: potential role of Lpp in inducing bubonic and pneumonic plague. Infect Immun 2008;76:1390-409.
 Meyer KF. Effectiveness of live or killed plague vaccines in man. Bull World Health Organ 1970;42:653-66.
 Cavanaugh DC, Elisberg BL, Llewellyn CH, Marshall JD, Jr., Rust JH, Jr., Williams JE, et al. Plague immunization. V. Indirect evidence for the efficacy of plague vaccine. J Infect Dis 1974;129:Suppl:S37-40.
 Williamson ED. Plague vaccine research and development. J Appl Microbiol 2001;91:606-8.
 Girard G. Plague. Annu Rev Microbiol 1955;9:253-76.
 Girard G. [Immunity in Plague. Acquisitions Supplied by 30 Years of Work on the "Pasteurella Pestis Ev" (Girard and Robic) Strain.]. Biol Med (Paris) 1963;52:631-731.
 Russell P, Eley SM, Hibbs SE, Manchee RJ, Stagg AJ, Titball RW. A comparison of Plague vaccine, USP and EV76 vaccine induced protection against Yersinia pestis in a murine model. Vaccine 1995;13:1551-6.
 Meyer KF, Smith G, Foster L, Brookman M, Sung M. Live, attenuated Yersinia pestis vaccine: virulent in nonhuman primates, harmless to guinea pigs. J Infect Dis 1974;129:Suppl:S85-12.
 Zilinskas RA. The anti-plague system and the Soviet biological warfare program. Crit Rev Microbiol 2006;32:47-64.
 Cornelius C, Quenee L, Anderson D, Schneewind O. Protective immunity against plague. Adv Exp Med Biol 2007;603:415-24.
 Feodorova VA, Pan'kina LN, Savostina EP, Sayapina LV, Motin VL, Dentovskaya SV, et al. A Yersinia pestis lpxM-mutant live vaccine induces enhanced immunity against bubonic plague in mice and guinea pigs. Vaccine 2007;25:7620-8.
 Blisnick T, Ave P, Huerre M, Carniel E, Demeure CE. Oral vaccination against bubonic plague using a live avirulent Yersinia pseudotuberculosis strain. Infect Immun 2008;76:3808-16.
 Ehrenkranz NJ, Meyer KF. Studies on immunization against plague. VIII. Study of three immunizing preparations in protecting primates against pneumonic plague. J Infect Dis 1955;96:138-44.
 Andrews GP, Heath DG, Anderson GW, Jr., Welkos SL, Friedlander AM. Fraction 1 capsular antigen (F1) purification from Yersinia pestis CO92 and from an Escherichia coli recombinant strain and efficacy against lethal plague challenge. Infect Immun 1996;64:2180-7.
 Anderson GW, Jr., Worsham PL, Bolt CR, Andrews GP, Welkos SL, Friedlander AM, et al. Protection of mice from fatal bubonic and pneumonic plague by passive immunization with monoclonal antibodies against the F1 protein of Yersinia pestis. Am J Trop Med Hyg 1997;56:471-3.
 Friedlander AM, Welkos SL, Worsham PL, Andrews GP, Heath DG, Anderson GW, Jr., et al. Relationship between virulence and immunity as revealed in recent studies of the F1 capsule of Yersinia pestis. Clin Infect Dis 1995;21 Suppl 2:S178-81.
 Davis KJ, Fritz DL, Pitt ML, Welkos SL, Worsham PL, Friedlander AM. Pathology of experimental pneumonic plague produced by fraction 1-positive and fraction 1-negative Yersinia pestis in African green monkeys (Cercopithecus aethiops). Arch Pathol Lab Med 1996;120:156-63.
 Quenee LE, Cornelius CA, Ciletti NA, Elli D, Schneewind O. Yersinia pestis caf1 variants and the limits of plague vaccine protection. Infect Immun 2008;76:2025-36.
 Une T, Brubaker RR. Roles of V antigen in promoting virulence and immunity in yersiniae. J Immunol 1984;133:2226-30.
 Lee VT, Tam C, Schneewind O. LcrV, a substrate for Yersinia enterocolitica type III secretion, is required for toxin targeting into the cytosol of HeLa cells. J Biol Chem 2000;275:36869-75.
 Motin VL, Nakajima R, Smirnov GB, Brubaker RR. Passive immunity to yersiniae mediated by anti-recombinant V antigen and protein A-V antigen fusion peptide. Infect Immun 1994;62:4192-201.
 Leary SE, Williamson ED, Griffin KF, Russell P, Eley SM, Titball RW. Active immunization with recombinant V antigen from Yersinia pestis protects mice against plague. Infect Immun 1995;63:2854-8.
 Anderson GW, Jr., Leary SE, Williamson ED, Titball RW, Welkos SL, Worsham PL, et al. Recombinant V antigen protects mice against pneumonic and bubonic plague caused by F1-capsule-positive and -negative strains of Yersinia pestis. Infect Immun 1996;64:4580-5.
 Jones SM, Griffin KF, Hodgson I, Williamson ED. Protective efficacy of a fully recombinant plague vaccine in the guinea pig. Vaccine 2003;21:3912-8.
 Hill J, Copse C, Leary S, Stagg AJ, Williamson ED, Titball RW. Synergistic protection of mice against plague with monoclonal antibodies specific for the F1 and V antigens of Yersinia pestis. Infect Immun 2003;71:2234-8.
 Zauberman A, Cohen S, Levy Y, Halperin G, Lazar S, Velan B, et al. Neutralization of Yersinia pestis-mediated macrophage cytotoxicity by anti-LcrV antibodies and its correlation with protective immunity in a mouse model of bubonic plague. Vaccine 2008;26:1616-25.
 Overheim KA, Depaolo RW, Debord KL, Morrin EM, Anderson DM, Green NM, et al. LcrV plague vaccine with altered immunomodulatory properties. Infect Immun 2005;73:5152-9.
 DeBord KL, Anderson DM, Marketon MM, Overheim KA, DePaolo RW, Ciletti NA, et al. Immunogenicity and protective immunity against bubonic plague and pneumonic plague by immunization of mice with the recombinant V10 antigen, a variant of LcrV. Infect Immun 2006;74:4910-4.
 Williamson ED, Sharp GJ, Eley SM, Vesey PM, Pepper TC, Titball RW, et al. Local and systemic immune response to a microencapsulated sub-unit vaccine for plague. Vaccine 1996;14:1613-9.
 Williamson ED, Eley SM, Stagg AJ, Green M, Russell P, Titball RW. A sub-unit vaccine elicits IgG in serum, spleen cell cultures and bronchial washings and protects immunized animals against pneumonic plague. Vaccine 1997;15:1079-84.
 Heath DG, Anderson GW, Jr., Mauro JM, Welkos SL, Andrews GP, Adamovicz J, et al. Protection against experimental bubonic and pneumonic plague by a recombinant capsular F1-V antigen fusion protein vaccine. Vaccine 1998;16:1131-7.
 Jones SM, Day F, Stagg AJ, Williamson ED. Protection conferred by a fully recombinant sub-unit vaccine against Yersinia pestis in male and female mice of four inbred strains. Vaccine 2000;19:358-66.
 Jones T, Adamovicz JJ, Cyr SL, Bolt CR, Bellerose N, Pitt LM, et al. Intranasal Protollin/F1-V vaccine elicits respiratory and serum antibody responses and protects mice against lethal aerosolized plague infection. Vaccine 2006;24:1625-32.
 Cornelius CA, Quenee LE, Overheim KA, Koster F, Brasel TL, Elli D, et al. Immunization with recombinant V10 protects cynomolgus macaques from lethal pneumonic plague. Infect Immun 2008;76:5588-97.
 Williamson ED, Flick-Smith HC, Waters E, Miller J, Hodgson I, Le Butt CS, et al. Immunogenicity of the rF1+rV vaccine for plague with identification of potential immune correlates. Microb Pathog 2007;42:11-21.
 Rocke TE, Smith S, Marinari P, Kreeger J, Enama JT, Powell BS. Vaccination with F1-V fusion protein protects black-footed ferrets (Mustela nigripes) against plague upon oral challenge with Yersinia pestis. J Wildl Dis 2008;44:1-7.
 Williamson ED, Flick-Smith HC, Lebutt C, Rowland CA, Jones SM, Waters EL, et al. Human immune response to a plague vaccine comprising recombinant F1 and V antigens. Infect Immun 2005;73:3598-608.
 Morris SR. Development of a recombinant vaccine against aerosolized plague. Vaccine 2007;25:3115-7.
 Huang J, D'Souza AJ, Alarcon JB, Mikszta JA, Ford BM, Ferriter MS, et al. Protective immunity in mice achieved with dry powder formulation and alternative delivery of plague F1-V vaccine. Clin Vaccine Immunol 2009;16:719-25.
 DuBois AB, Freytag LC, Clements JD. Evaluation of combinatorial vaccines against anthrax and plague in a murine model. Vaccine 2007;25:4747-54.
 Smiley ST. Immune defense against pneumonic plague. Immunol Rev 2008;225:256-71.
 Titball RW, Williamson ED. Yersinia pestis (plague) vaccines. Expert Opin Biol Ther 2004;4:965-73.
 Goodin JL, Nellis DF, Powell BS, Vyas VV, Enama JT, Wang LC, et al. Purification and protective efficacy of monomeric and modified Yersinia pestis capsular F1-V antigen fusion proteins for vaccination against plague. Protein Expr Purif 2007;53:63-79.
 Mizel SB, Graff AH, Sriranganathan N, Ervin S, Lees CJ, Lively MO, et al. Flagellin-F1-V fusion protein is an effective plague vaccine in mice and two species of nonhuman primates. Clin Vaccine Immunol 2009;16:21-8.
 Airhart CL, Rohde HN, Hovde CJ, Bohach GA, Deobald CF, Lee SS, et al. Lipid A mimetics are potent adjuvants for an intranasal pneumonic plague vaccine. Vaccine 2008;26:5554-61.
 Elvin SJ, Eyles JE, Howard KA, Ravichandran E, Somavarappu S, Alpar HO, et al. Protection against bubonic and pneumonic plague with a single dose microencapsulated sub-unit vaccine. Vaccine 2006;24:4433-9.
 Yamanaka H, Hoyt T, Yang X, Golden S, Bosio CM, Crist K, et al. A nasal interleukin-12 DNA vaccine coexpressing Yersinia pestis F1-V fusion protein confers protection against pneumonic plague. Infect Immun 2008;76:4564-73.
 Yamanaka H, Hoyt T, Bowen R, Yang X, Crist K, Golden S, et al. An IL-12 DNA vaccine co-expressing Yersinia pestis antigens protects against pneumonic plague. Vaccine 2009;27:80-7.
 Oyston PC, Williamson ED, Leary SE, Eley SM, Griffin KF, Titball RW. Immunization with live recombinant Salmonella typhimurium aroA producing F1 antigen protects against plague. Infect Immun 1995;63:563-8.
 Titball RW, Howells AM, Oyston PC, Williamson ED. Expression of the Yersinia pestis capsular antigen (F1 antigen) on the surface of an aroA mutant of Salmonella typhimurium induces high levels of protection against plague. Infect Immun 1997;65:1926-30.
 Leary SE, Griffin KF, Garmory HS, Williamson ED, Titball RW. Expression of an F1/V fusion protein in attenuated Salmonella typhimurium and protection of mice against plague. Microb Pathog 1997;23:167-79.
 Garmory HS, Griffin KF, Brown KA, Titball RW. Oral immunisation with live aroA attenuated Salmonella enterica serovar Typhimurium expressing the Yersinia pestis V antigen protects mice against plague. Vaccine 2003;21:3051-7.
 Yang X, Hinnebusch BJ, Trunkle T, Bosio CM, Suo Z, Tighe M, et al. Oral vaccination with salmonella simultaneously expressing Yersinia pestis F1 and V antigens protects against bubonic and pneumonic plague. J Immunol 2007;178:1059-67.
 Palin A, Chattopadhyay A, Park S, Delmas G, Suresh R, Senina S, et al. An optimized vaccine vector based on recombinant vesicular stomatitis virus gives high-level, long-term protection against Yersinia pestis challenge. Vaccine 2007;25:741-50.
 Chiuchiolo MJ, Boyer JL, Krause A, Senina S, Hackett NR, Crystal RG. Protective immunity against respiratory tract challenge with Yersinia pestis in mice immunized with an adenovirus-based vaccine vector expressing V antigen. J Infect Dis 2006;194:1249-57.
 Arlen PA, Singleton M, Adamovicz JJ, Ding Y, Davoodi-Semiromi A, Daniell H. Effective plague vaccination via oral delivery of plant cells expressing F1-V antigens in chloroplasts. Infect Immun 2008;76:3640-50.
 Plotkin SA, Koprowski H, Rupprecht CE. Rabies vaccine. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines 5th ed. Philadelphia Saunders,Elsevier, 2008: 687-714.
 World Health Organ (WHO). Expert Consultation on Rabies. Geneva; 2005 5-8 October 2004.
 World Health Organ (WHO). Rabies Facts in short. Geneva; 2006.
 Meslin FX, Fishbein DB, Matter HC. Rationale and prospects for rabies elimination in developing countries. Curr Top Microbiol Immunol 1994;187:1-26.
 Knobel DL, Cleaveland S, Coleman PG, Fevre EM, Meltzer MI, Miranda ME, et al. Re-evaluating the burden of rabies in Africa and Asia. Bull World Health Organ 2005;83:360-8.
 WHO. Initiative for Virus Research (WHO). Proceedings of the 7th Global Vaccine Research Forum. Bangkok; 2006
 Sudarshan MK, Madhusudana SN, Mahendra BJ, Rao NS, Ashwath Narayana DH, Abdul Rahman S, et al. Assessing the burden of human rabies in India: results of a national multi-center epidemiological survey. Int J Infect Dis 2007;11:29-35.
 Anderson LJ, Nicholson KG, Tauxe RV, Winkler WG. Human rabies in the United States, 1960 to 1979: epidemiology, diagnosis, and prevention. Ann Intern Med 1984;100:728-35.
 Messenger SL, Smith JS, Rupprecht CE. Emerging epidemiology of bat-associated cryptic cases of rabies in humans in the United States. Clin Infect Dis 2002;35:738-47.
 Fuenzalida E, Palacios R, Borgono JM. Antirabies Antibody Response in Man to Vaccine Made from Infected Suckling-Mouse Brains. Bull World Health Organ 1964;30:431-6.
 Plotkin SA, Wiktor T. Rabies vaccination. Annu Rev Med 1978;29:583-91.
 Montagnon BJ. Polio and rabies vaccines produced in continuous cell lines: a reality for Vero cell line. Dev Biol Stand 1989;70:27-47.
 Ajjan N, Pilet C. Comparative study of the safety and protective value, in pre-exposure use, of rabies vaccine cultivated on human diploid cells (HDCV) and of the new vaccine grown on Vero cells. Vaccine 1989;7:125-8.
 Suwansrinon K, Wilde H, Benjavongkulchai M, Banjongkasaena U, Lertjarutorn S, Boonchang S, et al. Survival of neutralizing antibody in previously rabies vaccinated subjects: a prospective study showing long lasting immunity. Vaccine 2006;24:3878-80.
 Nagarajan T, Rupprecht CE, Dessain SK, Rangarajan PN, Thiagarajan D, Srinivasan VA. Human monoclonal antibody and vaccine approaches to prevent human rabies. Curr Top Microbiol Immunol 2008;317:67-101.
 Bakker AB, Python C, Kissling CJ, Pandya P, Marissen WE, Brink MF, et al. First administration to humans of a monoclonal antibody cocktail against rabies virus: safety, tolerability, and neutralizing activity. Vaccine 2008;26:5922-7.
 Turner GS, Aoki FY, Nicholson KG, Tyrrell DA, Hill LE. Human diploid cell strain rabies vaccine. Rapid prophylactic immunisation of volunteers with small doses. Lancet 1976;1:1379-81.
 Kamoltham T, Khawplod P, Wilde H. Rabies intradermal post-exposure vaccination of humans using reconstituted and stored vaccine. Vaccine 2002;20:3272-6.
 Warrell MJ, Nicholson KG, Warrell DA, Suntharasamai P, Chanthavanich P, Viravan C, et al. Economical multiple-site intradermal immunisation with human diploid-cell-strain vaccine is effective for post-exposure rabies prophylaxis. Lancet 1985;1:1059-62.
 Briggs DJ, Banzhoff A, Nicolay U, Sirikwin S, Dumavibhat B, Tongswas S, et al. Antibody response of patients after postexposure rabies vaccination with small intradermal doses of purified chick embryo cell vaccine or purified Vero cell rabies vaccine. Bull World Health Organ 2000;78:693-8.
 Madhusudana SN, Anand NP, Shamsundar R. Economical multi-site intradermal regimen with purified chick embryo cell vaccine (Rabipur) prevents rabies in people bitten by confirmed rabid animals. Int J Infect Dis 2002;6:210-4.
 World Health Organ (WHO). Detailed Guidelines to pre- and post-exposure prophylaxis. Geneva 2007
 Madhusudana SN, Sanjay TV, Mahendra BJ, Sudarshan MK, Narayana DH, Giri A, et al. Comparison of safety and immunogenicity of purified chick embryo cell rabies vaccine (PCECV) and purified vero cell rabies vaccine (PVRV) using the Thai Red Cross intradermal regimen at a dose of 0.1 ML. Hum Vaccin 2006;2:200-4.
 Ambrozaitis A, Laiskonis A, Balciuniene L, Banzhoff A, Malerczyk C. Rabies post-exposure prophylaxis vaccination with purified chick embryo cell vaccine (PCECV) and purified Vero cell rabies vaccine (PVRV) in a four-site intradermal schedule (4-0-2-0-1-1): an immunogenic, cost-effective and practical regimen. Vaccine 2006;24:4116-21.
 World Health Organ (WHO) Rabies vaccines. Weekly Epidemiol Rec 2007;82:425-36.
 Dutta JK, Warrell MJ, Dutta TK. Intradermal rabies immunization for pre- and post-exposure prophylaxis. Natl Med J India 1994;7:119-22.
 Kamoltham T, Thinyounyong W, Phongchamnaphai P, Phraisuwan P, Khawplod P, Banzhoff A, et al. Pre-exposure rabies vaccination using purified chick embryo cell rabies vaccine intradermally is immunogenic and safe. J Pediatr 2007;151:173-7.
 Roukens AH, Vossen AC, van Dissel JT, Visser LG. Reduced dose pre-exposure primary and booster intradermal rabies vaccination with a purified chick embryo cell vaccine (PCECV) is immunogenic and safe in adults. Vaccine 2008;26:3438-42.
 Khawplod P, Wilde H, Benjavongkulchai M, Sriaroon C, Chomchey P. Immunogenicity study of abbreviated rabies preexposure vaccination schedules. J Travel Med 2007;14:173-6.
 Khawplod P, Wilde H, Sirikwin S, Benjawongkulchai M, Limusanno S, Jaijaroensab W, et al. Revision of the Thai Red Cross intradermal rabies post-exposure regimen by eliminating the 90-day booster injection. Vaccine 2006;24:3084-6.
 Khawplod P, Wilde H, Sriaroon C, Chomchey P, Kamolthum T, Sitprija V. One or three intradermal injections within one week for rabies pre-exposure immunization. Dev Biol (Basel) 2008;131:393-401.
 Cleaveland S, Kaare M, Tiringa P, Mlengeya T, Barrat J. A dog rabies vaccination campaign in rural Africa: impact on the incidence of dog rabies and human dog-bite injuries. Vaccine 2003;21:1965-73.
 Cliquet F, Barrat J, Guiot AL, Cael N, Boutrand S, Maki J, et al. Efficacy and bait acceptance of vaccinia vectored rabies glycoprotein vaccine in captive foxes (Vulpes vulpes), raccoon dogs (Nyctereutes procyonoides) and dogs (Canis familiaris). Vaccine 2008;26:4627-38.
 Boulanger JR, Bigler LL, Curtis PD, Lein DH, Lembo AJ, Jr. Comparison of suburban vaccine distribution strategies to control raccoon rabies. J Wildl Dis 2008;44:1014-23.
 Shwiff SA, Kirkpatrick KN, Sterner RT. Economic evaluation of an oral rabies vaccination program for control of a domestic dog-coyote rabies epizootic: 1995-2006. J Am Vet Med Assoc 2008;233:1736-41.
 Ramey PC, Blackwell BF, Gates RJ, Slemons RD. Oral rabies vaccination of a northern Ohio raccoon population: relevance of population density and prebait serology. J Wildl Dis 2008;44:553-68.
 World Health Organ (WHO). Guidelines for oral vaccination of dogs against rabies without cover. Geneva; 2007.
 Rupprecht CE, Barrett J, Briggs D, Cliquet F, Fooks AR, Lumlertdacha B, et al. Can rabies be eradicated? Dev Biol (Basel) 2008;131:95-121.