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Vaccine Profile

30 years of rabies vaccination with Rabipur: a summary of clinical data and global experience

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Abstract

Rabies poses a threat to more than 3.3 billion people worldwide and is estimated to cause about 60,000 deaths a year. However, according to the WHO, it is still one of the most neglected diseases in developing countries. Human rabies vaccinations are critical components of pre-exposure and post-exposure prophylaxis. Rabipur®, the first purified chick embryo cell-culture vaccine, was licensed in Germany in 1984, and later in more than 60 countries worldwide. The immunogenicity, efficacy and safety of Rabipur have been assessed in numerous clinical trials in pre- and post-exposure regimens, using both intramuscular and intradermal routes of administration. The trial populations have involved adults and children, including healthy volunteers and individuals bitten by laboratory-proven rabid animals, malnourished children and immunocompromised individuals. Extensive, worldwide clinical experience with Rabipur over the past 30 years has shown the vaccine to be immunogenic, effective and generally well tolerated.

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Erratum

Rabies is a zoonotic viral disease of mammals that is transmitted from animals to humans, although there have been exceptional reported cases of direct human-to-human transmission and indirect transmission via infected transplants Citation[1–3]. The rabies virus is a member of the genus Lyssavirus, which belongs to the family of Rhabdoviridae. The incubation period is typically 1–3 months, but can vary from a few days to more than 1 year Citation[1,4]. Cases of up to 6 years incubation period have been discussed Citation[5]. Initial symptoms are usually nonspecific, including fever and headache. Unfortunately, as the virus enters into the CNS an acute encephalitis or meningoencephalitis develops. This can result in various forms of neurological and psychological manifestations, usually followed by paralysis and coma, and finally death Citation[1]. Once clinical symptoms of the disease develop, rabies is nearly always fatal Citation[6].

Rabies is known to be present on all continents (except Antarctica) and infects both wild and domestic animals Citation[7]. This disease poses a potential threat to more than 3.3 billion people and is estimated to cause about 60,000 deaths each year Citation[7,8]. Given that reliable data are unavailable in many regions due to under or no reporting and inadequate surveillance, it is estimated that in some countries the incidence of rabies could be as much as 15-times higher than that of official reports Citation[1,9]. According to the WHO, rabies is still one of the most neglected diseases in developing countries Citation[10]. The majority of human fatalities occur in Asia and Africa where rabies is mainly transmitted by dog bites. In contrast, human rabies in Europe and North America is rare; countries in these regions are either free of terrestrial or canine rabies, but the virus circulates in other mammalian animal reservoirs, including bats. In Latin America and the Caribbean, cases of human rabies transmitted by dogs have been significantly reduced in the past 20 years Citation[1,8].

While in countries where rabies is endemic, all people are at risk of being exposed. Children in these countries have the highest risk due to several behavioral factors. Examples include children’s attraction toward animals, lack of awareness of potential dangers and reluctance to report bites or scratches. Moreover, their small stature makes them more susceptible to be bitten in the face, head and hand, which decreases the incubation period of the rabies virus upon infection. In fact, between 30 and 50% of post-exposure prophylaxis (PEP) are reported to be provided to children Citation[1,11].

Rabies prevention and control consists of different methods including wild and domestic animal vaccination programs, animal birth control, responsible pet ownership, and rabies education and awareness. Human rabies vaccination is one of the most important elements of preventing rabies in humans. Officially recommended pre-exposure prophylaxis (PrEP) and PEP regimens should be followed before potential or after actual exposure, respectively Citation[1,8].

Rabies vaccines – historical development

Originally, rabies vaccines were derived from animal nerve or brain tissue, so-called nerve tissue vaccines (NTVs). Nowadays, rabies vaccines are mostly cell-culture and embryonated egg-based vaccines (jointly referred to as CCEEVs) and only a few countries still use NTVs Citation[8]. The first reported rabies vaccination with an NTV was in 1885 when Louis Pasteur successfully treated a young boy who had been severely bitten by a rabid dog with a series of vaccinations consisting of a spinal cord suspension of increasing virulence derived from rabid rabbits Citation[12]. Improvements were later made to the vaccine’s safety by inactivating the virus with phenol. However, there were still severe side effects following administration of NTVs, including some cases of paralysis and even death. A major factor is due to patient hypersensitivity to myelin Citation[12,13]. Nerve tissue-derived vaccines produced from brains of suckling animals were later used as these contain smaller amounts of myelin Citation[14]. A modified preparation produced with suckling mouse brain tissue is still used in a small number of Latin American countries, and NTVs from virus-infected goat or sheep brain tissue are still utilized in a few countries in Asia and Africa Citation[15]. However, as NTVs can induce severe adverse reactions and are less immunogenic than CCEEVs, the WHO does not recommend the production and use of rabies NTVs Citation[8,16].

Rabies vaccine production later focused on finding sources of virus propagation in materials free of neural tissue Citation[17]. This led to the development of embryonated egg-based and cell-culture-based vaccines. For embryonated duck egg-based rabies vaccine, the complete embryo is utilized for virus propagation. In contrast, cell-culture-based vaccines contain the rabies virus that has been propagated in cell substrates (e.g., primary hamster kidney cells, human diploid cells, chick embryo cells or Vero cells) Citation[8,18–21]. Research also addressed which viral strains should be used. Investigations in humans using low-egg-passage (LEP) Flury virus showed that the Flury virus vaccine could be used without ‘untoward effects’ for the immunization of humans against rabies – although at that time (the early 1950s) the vaccine was not highly immunogenic Citation[22]. Experiments with a high-egg-passage Flury vaccine resulted in better immunogenicity, but were still inferior to NTVs Citation[23]. An inactivated duck embryo virus vaccine appeared to be more promising, but its immunizing potency was again not as high as that of NTVs Citation[17].

In the late 1950s, work began on cultures of human fetal fibroblasts, which were diploid cells that had a finite lifetime. Fetal fibroblasts were soon shown to be susceptible to human viruses and free of latent viruses Citation[24]. By the early 1960s, the highly immunogenic human diploid cell line WI-38 was being used for rabies virus propagation Citation[24,25]. With some modifications (including a switch to the MRC-5 cell line), the resulting rabies vaccine produced using human diploid cells vaccine (HDCV) had a better tolerability profile and induced a far greater immune response in animals and humans than any other vaccine of that time Citation[25–27]. Indeed, Garner and colleagues reported that in their clinical experience, HDCV was associated with less severe and persistent local inflammation, lymphadenopathy, headaches and fever than the duck embryo virus vaccine Citation[28]. Human diploid cells vaccine was first licensed for pre- and post-exposure immunization in Europe in 1976 and in the USA in 1980 and is still available now Citation[27].

Large-scale production of rabies virus in human diploid cell strains is a complex process with a low virus yield in comparison to other cell systems. It results in high production costs and a limited output of vaccine for HDCV Citation[29]. Over subsequent years, a series of different vaccines have been developed with similar immunogenicity to HDCV Citation[12]. Licensed in 1985, a purified Vero cell rabies vaccine (PVRV) has comparable immunogenicity to HDCV with the advantages of a better safety profile Citation[30].

Investigations into a purified chick embryo cell-culture vaccine (PCECV) for rabies started in the late 1970s in Marburg, Germany Citation[28]. In the 1980s, an immunogenic PCECV containing inactivated rabies virus (LEP Flury strain) was developed. In a series of animal laboratory tests, PCECV showed comparable immunogenicity and tolerability to that of HDCV Citation[29]. In human studies, PCECV induced similar immunogenicity to HDCV Citation[31–34]. The purified chick embryo cell-culture vaccine was subsequently licensed in Germany in 1984 as Rabipur® (Novartis Vaccines). The availability of HDCV, PVRV and PCECV (Rabipur) has enabled dosing schedules to be vastly reduced and side effects minimized compared with NTVs Citation[35]. Based on these cell culture production platforms, recently other rabies vaccines have been developed. Some of them are using different virus strains Citation[36–38].

Purified chick embryo cell-culture vaccine – Rabipur

Rabipur is produced using Flury LEP rabies virus strain grown in a culture of primary chick embryo fibroblast cells using specific pathogen-free eggs in compliance with current applicable pharmacopeia and with WHO requirements. The Flury LEP rabies virus is inactivated with β-propiolactone, purified via continuous density-gradient centrifugation, resulting in a highly concentrated formulation stabilized with polygeline (a processed gelatin product), and then lyophilized Citation[39]. Rabipur is produced in two WHO pre-qualified manufacturing facilities: Marburg, Germany and Ankleshwar, India Citation[40]. In Marburg, Germany, a new state-of-the-art manufacturing facility for Rabipur has been approved as of 2014. Batches of Rabipur from the two sites have been shown to be clinically comparable: noninferiority in immunogenicity and tolerability of the vaccine produced in India to the vaccine produced in Germany has been demonstrated Citation[41,42]. Additionally, all batches compared reach or exceed the minimum potency of ≥2.5 international units per single intramuscular (IM) dose, as specified by the WHO and approved by regulatory authorities Citation[8]. PCECV has been found to have 1000-fold lower concentration (0.024 mg/dose) of human serum albumin, which is a stabilizer and a considerable component in most vaccines, compared to PVRV, HDVC and primary hamster kidney vaccines Citation[43]. Moreover, tested batches of PCECV were shown to contain Flury LEP rabies virus strain with no deviations from published genetic sequences Citation[43]. PCECV is marketed globally as Rabipur, with a few exceptions: in South Africa and Namibia it is marketed as Rabipor (licensed in 2000) and in the USA and Canada as RabAvert® (licensed in 1997 and 2003, respectively). Throughout this manuscript, PCECV will be referred to as Rabipur.

Vaccination regimens

Rabies differs from many other infectious diseases in that, despite following exposure to the infectious agent, clinical manifestation of the disease may be prevented through timely immunization (in adherence with WHO protocols) as long as clinical symptoms have not developed Citation[8,44]. Thus, both PEP and PrEP regimens are effective in immunizing against rabies Citation[45].

Post-exposure prophylaxis

The key immunological objective of PEP is to neutralize and destroy the rabies virus inoculated in the victim’s body immediately following exposure so that clinical manifestation of rabies does not develop. PEP has three main components: wound treatment, vaccine administration and rabies immunoglobulin (RIG) administration, if indicated Citation[8,44]. The WHO recommendations for PEP depend on the type of contact with the suspected rabid animal and the vaccination status of the individual based on three categories of risk and exposure (I-III). Definition of categories of exposure and the use of rabies biologicals are as follows:

  • Category I is insignificant or no exposure to the animal and therefore requires no prophylaxis;

  • Category II is minor scratches or abrasions without bleeding and requires vaccine; and

  • Category III is transdermal bite or scratches or contamination of mucous membrane or any exposure to bats, which would require use of RIG plus vaccine Citation[8,44].

In deploying PEP, the immunization schedule should begin as soon as possible following exposure and must be followed exactly as recommended, regardless of when the patient comes in for treatment after the initial contact. In individuals who have not been vaccinated with the rabies vaccine or individuals with uncertain immune status, Rabipur is administered via IM injection using the Essen five-dose regimen (one dose on Days 0, 3, 7, 14 and 28) or the Zagreb four-dose regimen (two doses on Day 0, followed by one dose on Days 7 and 21). Recently, Advisory Committee on Immunization Practices and WHO have amended their PEP recommendations to reduce the Essen five-dose regimen to four doses (one dose on Days 0, 3, 7 and 14). This shortened regimen may be used as an alternative for healthy, fully immune competent, exposed people provided they receive wound care plus RIG in category III as well as in category II exposures and a WHO-prequalified rabies vaccine Citation[8,46]. This, however, until today has not been reflected in the labels of any rabies vaccine. In countries where the intradermal (ID) route of administration has been endorsed by national regulatory authorities, the WHO recommends the ID 2-site regimen (updated Thai Red Cross; two doses of 0.1 ml ID at two different lymphatic drainage sites on Days 0, 3, 7 and 28) Citation[8,16].

Pre-exposure prophylaxis

PrEP simplifies post-exposure care by eliminating the need for RIG and reducing the number of doses of vaccine needed for immediate post-exposure immunization. Individuals who have previously been vaccinated with a rabies vaccine will only need two doses of Rabipur for PEP (given on Days 0 and 3) as soon as possible after exposure. For PrEP, immunization consists of a 3-dose IM regimen of Rabipur (administered on Days 0, 7 and 21 or 28) into a deltoid muscle (anterolateral region of the thigh in small children). The three-dose regimen can also be administered ID, in countries where ID route of administration is endorsed by national regulatory authorities Citation[8,45].

Rabipur clinical trials

The immunogenicity, efficacy and safety of Rabipur have been assessed in more than 50 clinical trials since 1983 in both PEP and PrEP regimens, using IM as well as ID administration. The trial populations have comprised of adults and children aged 12 months and older. Subjects included healthy individuals, individuals bitten by suspect or laboratory-proven rabid animals, malnourished children and immunocompromised persons. Summaries and overviews of relevant clinical trial results are provided in , and individual trials and published case studies are provided exemplarily in detail in the review text.

Table 6. Summary of Rabipur efficacy following PEP administration.

Table 1. Summary of Rabipur intramuscular PEP and PrEP immunogenicity and safety studies in adults.

Table 2. Summary of Rabipur intradermal PEP and PrEP immunogenicity studies in adults.

Table 3. Rabipur PEP and PrEP immunogenicity and safety studies in children.

Table 4. Rabipur immunogenicity in HIV-infected individuals.

Table 5. Rabipur PrEP immunogenicity following a booster dose in adults and children.

At the time of the vaccine development, a PEP six-dose Essen regimen was officially recommended by the WHO for all cell-culture rabies vaccines. Consequently, Rabipur was initially assessed in clinical trials with a six 1.0 ml/dose IM Essen regimen for PEP and was licensed as such. According to WHO guidelines, the PEP six-dose Essen regimen produced an adequate antibody response (specific antibody level of ≥0.5 IU/ml) Citation[8,44,45]. Alternatively, the Zagreb regimen was developed with an abbreviated schedule (2-1-1) of two doses on Day 0 and one dose on Days 7 and 21. Over time, the sixth dose of the Essen regimen on Day 90 became optional and, in 1992, the WHO published new guidelines that recommended a five-dose Essen regimen (without the dose on Day 90) for which Rabipur was later indicated Citation[47].

Immunogenicity in PEP & PrEP regimens

Rabipur has been investigated extensively in PEP and simulated PEP regimens in humans and has a well-established immunogenicity and tolerability profile for both the Essen and Zagreb regimens. An overview and summary of the relevant clinical trials investigating the immunogenicity of Rabipur in PEP and PrEP IM regimens is provided in .

A pivotal immunogenicity study assessed several vaccination regimens in 88 healthy volunteers; 15 volunteers received Rabipur in a simulated PEP six-dose Essen regimen (a single 1.0 ml IM dose on Days 0, 3, 7, 14, 30 and 90); another 14 volunteers received Rabipur in the PEP five-dose Essen regimen (a single 1.0 ml IM dose on Days 0, 3, 7, 14 and 30). Rabies virus neutralizing antibody (RVNA) concentration of ≥0.5 IU/ml was achieved in all subjects by Day 14, which has been well established as an adequate antibody response after vaccination Citation[48]. Volunteers noted the following reactions to the vaccine: general systemic reactions (31.2%); local adverse reactions – mostly mild (56.5%); moderate or severe general reactions, including fatigue, headache and dizziness (15.1%); and moderate or severe local reactions including pain, induration or redness (16.4%).

The immunogenicity of Rabipur when administered using the WHO-recommended Zagreb regimen has been demonstrated in several studies. In one trial, 32 individuals were randomly assigned to receive Rabipur and 50 received PVRV with two doses on Day 0 and a single dose on Days 7 and 21. All subjects achieved RVNA concentrations ≥0.5 IU/ml within 14 days of initial vaccination and showed no significant difference in the immune response between Rabipur and PVRV Citation[49]. These findings support those of others where administration of Rabipur IM using the Zagreb regimen evoked a rapid and high-titer antibody response, peaking at Day 14 Citation[32].

Historically, the simultaneous administration of RIG together with rabies vaccines for PEP raised discussion on possible interference of RIG on the patient’s own active immune response to the vaccine. A study using human rabies immunoglobulin at the recommended concentration of 20 IU/kg observed partial interference with the initial active development of RVNA when administered concomitantly with different types of rabies vaccines applied by the Zagreb regimen Citation[50]. When Rabipur was administered in different IM and ID regimens for PEP simultaneously with either equine rabies immunoglobulin or human rabies immunoglobulin, initial effects on antibody concentrations were observed in some instances. However, none of this interference was clinically relevant as RVNA concentrations were always above the adequate level of 0.5 IU/ml Citation[51–55].

Rabipur PrEP regimens have been shown to be immunogenic and well tolerated when administered in humans . In a pivotal PrEP study in healthy adults, Rabipur was given in a three-dose series and followed by a 2-year booster. Vaccination with Rabipur via an IM or ID regimen resulted in adequate immune response by Day 28, which was sustained at Day 365 Citation[33]. Comparable results were found in a similar study comparing Rabipur with HDCV Citation[34].

Immunogenicity following ID administration

The standard route of administration of Rabipur is IM injection into the deltoid muscle of adults or the anterolateral region of the thigh in small children Citation[56]. However, Rabipur may be administered ID in countries where this route is endorsed by national regulatory authorities Citation[8]. ID administration is a more economic and antigen-saving alternative to IM administration as it requires 0.1 ml of vaccine per ID dose, in contrast to 1.0 ml per IM dose Citation[8]. In PrEP, Rabipur induces slightly lower levels of RVNA when administered ID compared with IM Citation[33]. However, for PEP regimens, RVNA levels following ID and IM administration of Rabipur are comparable Citation[52].

The immunogenicity of 0.1 ml Rabipur for ID administration has been well established in clinical trials . A study of 211 patients with WHO category II or III rabies exposure in Thailand was designed to assess whether Rabipur for ID PEP treatment could effectively be reduced to 0.1 ml per site. Geometric mean RVNA concentrations on Day 14 after Rabipur ID (0.1 ml at two sites on Days 0, 3 and 7; one site on Days 30 and 90) were noninferior to patients who received IM Rabipur (1.0 ml on Days 0, 3, 7, 14, 30 and 90) and were ≥0.5 IU/ml Citation[52]. This study employed the Thai Red Cross regimen, which was the former official WHO-endorsed ID regimen. However, over the years, the dosing schedule for ID administration has evolved as evidence from clinical trials has become available. The WHO now recommends the updated Thai Red Cross 2-site regimen as the most cost–effective and widely used ID regimen: 0.1 ml at two different ID sites on Days 0, 3, 7 and 28 Citation[8].

The WHO-defined minimum vaccine potency of 2.5 IU per IM dose has been established as effective for use in ID administration as well Citation[51]. A study by Beran and colleagues investigated whether the 1.0-ml dose of Rabipur for IM administration was still sufficient to induce an adequate antibody response after a several-fold dilution and following 0.1 ml ID administration. The study showed that an adequate RVNA response (≥0.5 IU/ml) was elicited and maintained when Rabipur was administered via the ID route of administration in the Thai Red Cross 2-site regimen. These data confirm that the WHO-recommended minimum potency of 2.5 IU for IM administration is adequate also for the 0.1 ml ID dosing regimen Citation[51].

Immunogenicity in children

Children in rabies endemic countries are at particular high risk due to their attraction toward animals, lack of awareness of potential dangers, potential reluctance to report bites or scratches and their small stature (making them more susceptible to face, head and hand bites from animals, which decreases the incubation period). Exposure to the rabies virus occurs disproportionately in children: on average, 40% of PEP is administered to children aged 5–14 years Citation[1]. A number of clinical trials have demonstrated Rabipur to be immunogenic with an acceptable safety profile in children for both PEP and PrEP .

A study in children (n = 11) aged 2–15 years who had single IM doses of Rabipur (1.0 ml) on Days 0, 7 and 28 for PrEP showed RVNA concentrations ≥0.5 IU/ml by Day 14. No serious adverse events (SAEs) were reported after vaccination Citation[57]. Another study (n = 175) comparing three IM doses of Rabipur (reconstituted in 1.0 ml or 0.5 ml diluent) or PVRV with single doses on Days 0, 7 and 28 for PrEP in children aged 6–13 years demonstrated that RVNA concentrations were ≥0.5 IU/ml by Day 49 Citation[58]. Similar findings have been observed in children aged 12–18 months receiving IM or ID Rabipur (1.0 or 0.1 ml, respectively) on Days 0,7 and 28 for PrEP, with concomitant administration of Japanese encephalitis vaccine Citation[59]. Rabipur has also demonstrated immunogenicity in older children when administered by ID injection for PrEP Citation[56,60]. Rabipur is generally well tolerated in children; reported typical adverse reactions in clinical trials included fever, tenderness, and pain and redness at the injection site. No serious adverse reaction related to the vaccine occurred Citation[57,61–64].

A PEP study assessing Rabipur immunogenicity was carried out in children bitten by either confirmed or suspected rabid animals (mainly dogs, followed by monkeys, cats and mongoose). Two hundred and seventy one children aged 1–13 years received PEP on Days 0, 3, 7, 14, 30 and 90. The serological response was adequate, with all children demonstrating RVNA concentration of ≥0.5 IU/ml with a maximum immune response measured 10–15 days after the last vaccination. The vaccine was well tolerated and no failures were observed Citation[65].

The anamnestic response to simulated post-exposure booster doses of Rabipur has also been demonstrated in children aged 5–8 years at the time of primary vaccination. Two booster doses (Days 0 and 3) of Rabipur were administered ID 1, 3 or 5 years after three primary vaccination doses and resulted in adequate RVNA concentrations (≥0.5 IU/ml) in all children (n = 312) by Day 14 after booster Citation[61].

A clinical case study reported on the vaccination of a newborn baby with Rabipur after her mother developed clinical rabies during pregnancy following a dog bite 3 months prior to giving birth. A healthy female baby was delivered (gestational age 40 weeks), following which the baby received a total of five doses of Rabipur: 1.0 ml IM at birth and a four-dose series (Days 3, 7, 14 and 30). Seven days after the final dose of Rabipur, the baby’s RVNA level was 2.34 IU/ml and, at the age of 2 years, the child was healthy and developing normally Citation[66].

Immunogenicity in malnourished children

Asia is home to over half of the world’s malnourished children. Approximately 50% of pre-school age children suffer mild-to-moderate malnutrition, and over 90% of reported human rabies deaths occur in Asia Citation[63]. Depending on the type of vaccine administered, studies examining the immune response to vaccination in children suffering from malnutrition have reported varying results. Antibody responses to BCG for tuberculosis, and in some cases polio vaccines, have been reported to be depressed in children with severe malnutrition, whereas measles vaccine appears to be efficacious even in malnourished children Citation[67]. In a study by Sampath and colleagues, 45 malnourished children aged 8 months to 16 years who presented to the anti-rabies clinic in Hyderabad, India, for PEP were enrolled to be investigated for their response to Rabipur. Thirty six children received five doses, three received four doses and six received less than four doses of the vaccine. The 39 who received four or more doses made it through to the per-protocol set Citation[63]. All bites were evaluated as category II or III, in accordance with the WHO criteria Citation[8]. All children had developed RVNA levels ≥0.5 IU/ml by Day 14. There was no significant difference in RVNA concentrations between the malnutrition categories – immune response to Rabipur was independent of the extent of malnutrition. In addition, there were no SAEs reported, indicating that Rabipur is well tolerated in malnourished children Citation[63].

Immunogenicity in pregnancy

Rabies presents an intermediate risk to the unborn fetus of pregnant women Citation[68,69]. Whether the rabies virus can cross the placenta remains uncertain due to confounding reports. A report from 1977 describes a pregnant woman infected with rabies who delivered a premature baby before dying. Although the baby was not vaccinated, it did not develop rabies. Other publications have also suggested that placental transmission of rabies virus in humans is highly improbable Citation[68]. In 1981, however, a woman who was 9 months pregnant presented to a hospital 34 days after being bitten by a rabid dog. Two days after the mother was admitted to the hospital, the baby was born following induction of labor and died suddenly 40.5 h later. The autopsy confirmed that both mother and baby had rabies. This was the first reported case of human rabies acquired by placental transmission Citation[69].

The administration of Rabipur in pregnant women for PEP has been documented in a retrospective case series on two pregnant women who had WHO category III exposure to a suspected rabid animal at gestational Week 12. Each of the pregnant women got a total of five doses of Rabipur: 1.0 ml IM on Days 0, 3, 7, 14 and 28 (Essen regimen) and equine rabies immunoglobulin. Both vaccine and equine rabies immunoglobulin were well tolerated with no reports of systemic or local AEs. The women had normal deliveries of healthy babies with no evidence of congenital abnormalities Citation[70]. There is a clear consensus that pregnancy is not a contraindication to rabies PEP Citation[71].

Immunogenicity in immunocompromised individuals

HIV-infected individuals generally have suboptimal immune responses to several commonly used vaccines Citation[72,73]. Rabies vaccination differs from other immunizations in that it represents prophylaxis of development of a fatal disease after virus exposure. However, there has been a concern over whether the WHO-recommended PEP regimens provide adequate RVNA levels in HIV-infected persons exposed to the rabies virus Citation[74]. Both IM and ID rabies vaccination regimens have been reported to be less immunogenic in HIV-infected patients Citation[71,74–78].

In HIV-infected individuals, administration of Rabipur (five-dose IM regimen; 1.0 ml single doses on Days 0, 3, 7, 14 and 30) for PEP resulted in RVNA concentrations that were lower in HIV-infected people than in uninfected controls . While the response of RVNA was 7.75 IU/ml in the control group of healthy volunteers, levels were 1.09 IU/ml in asymptomatic HIV patients and 0.31 IU/ml in symptomatic patients at Day 14. The percentage of patients with RVNA ≥0.5 UI/ml was 100% in the control group, 64% in the asymptomatic group and 25% in the symptomatic HIV patients at Day 14 Citation[79,80]. The development of antibody levels in severely immunocompromised patients should therefore be checked 14 days after the initiation of a rabies vaccination schedule Citation[45] and the guidance on the product label should be followed Citation[56].

Immunogenicity of booster doses

The immunogenicity of Rabipur following a booster dose has been proven in PrEP in healthy volunteers who have previously received Rabipur or HDCV Citation[34]. In addition, the anamnestic response to booster doses of Rabipur has been demonstrated 14 years after the last vaccination Citation[81]. Individuals were vaccinated with either IM or ID Rabipur according to a three-dose PrEP schedule, followed by a 1.0 ml IM booster dose 2 years later. Subjects did not receive any further booster doses. Fourteen years later, 10 individuals who provided serum samples for analysis had adequate RVNA titers of >1:5, as defined by the Advisory Committee on Immunization Practices, and received one 1.0 ml IM booster dose Citation[71]. Blood samples taken 24–45 days following the second booster demonstrated a high anamnestic response of an approximate 10-fold increase in RVNA titers Citation[81]. Another study demonstrated RVNA levels ≥0.5 IU/ml in individuals at least up to 6 years following PrEP or PEP Rabipur regimens Citation[82].

Immunogenicity in nonclassical bat lyssavirus strains

Although the majority of human cases of rabies occur after exposure to classical rabies virus transmitted by dog bite, bat-transmitted nonclassical rabies strains, such as European bat lyssavirus type I (EBLV-I) and II and Australian bat lyssavirus, represent a source of human rabies. The immunogenicity (cross-neutralizing activity) of Rabipur to these related lyssavirus species was assessed in a laboratory study in which samples from healthy volunteers who had received Rabipur in a simulated ID PEP regimen as part of a separate clinical trial were analyzed. Rabipur induced adequate neutralizing antibodies to EBLV-1, EBLV-II and Australian bat lyssavirus in 97, 100 and 100% of samples, respectively Citation[83].

Efficacy

Although there is no specific level of RVNA that is recognized as being ‘protective’ against rabies in humans, the WHO recommends an RVNA concentration of ≥0.5 IU/ml as being proof of an adequate immune response to vaccination Citation[8,44,45]. However, while immunogenicity of a vaccine is a surrogate parameter, and no correlate of protection can be established in humans for obvious ethical reasons, vaccine efficacy can be assessed by investigating whether survival after an exposure has occurred. This is ideally done by looking at survival after initiation of proper PEP following category II or III exposure to a laboratory-confirmed rabid animal Citation[45]. Real survival data are available following administration of Rabipur to rabies-exposed patients . A prospective clinical trial assessing the efficacy of a 0.1-ml dose of Rabipur administered ID was conducted in 113 patients presenting with category III exposure from laboratory-confirmed rabid animals. Patients in the study were vaccinated with 0.1 ml Rabipur via the Thai Red Cross regimen and monitored monthly for 1 year post exposure. The vaccine was well tolerated and no SAEs were reported. All patients survived 1 year post exposure, confirming the efficacy of Rabipur Citation[53].

A summary of the efficacy data of Rabipur following PEP administration in response to animal bites is listed in . These studies show that all patients who received Rabipur following exposure to a rabid animal survived over the indicated observation period. This demonstrated efficacy comes from robust data collected from several hundred patients of different ages, including children, across many trials.

Rabipur post-marketing surveillance

The safety of PEP and PrEP with Rabipur has been assessed in a 10-year post-marketing surveillance study in India in 1289 individuals including children from 1 year of age. Vaccination with Rabipur was well tolerated, with only 4% of subjects reporting AEs, all of which were mild to moderate. The most commonly reported local adverse reactions in subjects were injection-site pain (n = 26, 2.1%) and injection-site induration (n = 14, 1.1%). Mild fever (37.2–37.8°C) occurred in six subjects (0.5%), which lasted 12–24 h following the third or fourth vaccination Citation[64].

A 2007 safety review of RabAvert presented an analysis of post-licensure safety reports in the USA from 1997 to 2005. The analysis, which used data collected via the Vaccine Adverse Event Reporting System, showed that of approximately 1.1 million doses of vaccine distributed in the USA during the study timeframe there were 336 AEs reported after Rabipur administration – approximately 30 events per 100,000 doses. Twenty-four (7%) of the AEs were considered serious by the reporters and there were no reports of death. The authors concluded that the evaluation of Vaccine Adverse Event Reporting System reports did not suggest a high frequency or unusual pattern of serious or other medically important AEs, and most AEs were nonserious and consistent with pre-licensure safety data Citation[84].

Nearly 30 years of global usage of Rabipur confirms the well-balanced safety and tolerability profile seen in clinical trials. The overall adverse drug reaction reporting rate for Rabipur in the past 28.5 years is approximately 12.3 events per 100,000 doses sold. The vast majority (nearly 80%) of reported events from Asia, Europe and the USA were nonserious reactions known from clinical trials. The Medical Dictionary for Regulatory Activities, a clinically validated international terminology dictionary, is organized by System Organ Class (SOC) under which most of the reported Rabipur adverse drug reactions are classified. Characteristics of SOC include general disorders and administration site conditions (24%), nervous system disorders (18%) or musculoskeletal and connective tissue disorders (10%). Within these SOCs, the most often reported symptoms were systemic reactions, such as headache, dizziness, influenza-like illness and associated symptoms (e.g., fever, asthenia and myalgia), and local injection-site-related reactions (e.g., redness, swelling and pain). Reports on serious adverse drug reactions were in line with what is described in the current Rabipur Core Safety Information or were reactions for which a causal relationship to Rabipur has not been established. The general safety profile of Rabipur is as expected for an inactivated vaccine and remains consistent with that shown in clinical trials.

Rabies PEP failure

There are reported incidences of people exposed to rabies virus developing clinical rabies despite the administration of PEP. However, investigation into these cases shows that for the majority of patients there was an omission of at least one of the essential steps of PEP (wound treatment, administration of RIG and complete course of vaccine) Citation[85–89]. Physicians should be advised that immediate and correct PEP management without delay according to official recommendations is essential for patient survival.

However, there are very rare reported cases in which clinical rabies has developed in immunologically healthy people despite apparently correct PEP regimen, including wound treatment and timely administration of RIG and vaccine. A systematic review reported a total of eight probable true vaccine failure cases in which Rabipur was administered in one case, Rabipur and PVRV were given in a second case and an unknown vaccine in a third case Citation[89]. More recently, a case of atypical initial clinical rabies symptoms that led to delayed diagnosis was reported. The patient died despite appropriate PEP and administration of Rabipur Citation[90].

Expert commentary

This review covers clinical trials that have contributed in a relevant and significant way to the clinical development of Rabipur and to the definition of appropriate rabies vaccination regimens. The development of rabies vaccines has come a long way, and cell-culture rabies vaccines, such as Rabipur, have the benefit of inducing less severe adverse reactions compared to formerly used NTVs. Not only does Rabipur induce an immune response after IM administration, but it is also capable of stimulating a comparable immune response via an ID route. Moreover, ID administration has significantly contributed to the affordability of rabies vaccines in endemic, developing countries where it is endorsed by national health authorities. Due to replacement of NTVs with cell-culture vaccines such as Rabipur, several countries in Asia have come up with novel ID administration techniques to compensate for logistical and economic challenges. With this shift to cell-culture vaccines, the management of rabies represents a significant unmet global need, particularly in endemic, developing countries. Despite the availability of effective vaccines, the number of human deaths from rabies is unacceptably high Citation[91]. Human rabies vaccination is a critical component of the PrEP and PEP regimens that should be followed before potential or after actual exposure to the rabies virus. Three decades of widespread clinical use of Rabipur confirms its immunogenicity and tolerability for both pre- and post-exposure vaccination regimens among diverse populations. Wider use of human rabies vaccination for PrEP and PEP in conjunction with programs to eradicate rabies from animal populations would be the right direction in reducing the burden of disease. The most vulnerable populations to benefit from such collaborated efforts are children, particularly in developing countries. Technology exists to protect against rabies. If rabies is left unmanaged, it is virtually 100% fatal.

Five-year view

For over three decades, global and local health organizations and institutions have engaged in the prevention and control of rabies, particularly in low- and middle-income countries. The value of rabies vaccination remains unchanged, especially considering that several countries aim to become rabies-free from 2020 to 2025. Widespread use of ID administration and shorter ID PEP regimens could become a more common practice in other countries in Asia and elsewhere. To support countries in their efforts to eliminate rabies, there is a need to continue with and strengthen measurements such as enhancing awareness, rabies education, teaching general prevention measures and providing appropriate rabies immunization based on recommended vaccination regimens. The pathways to rabies vaccine development have produced successful prophylaxis prevention and treatment used to save individuals exposed to rabies. Furthermore, NTVs may be phased out in the next 5 years in the remaining few countries that still use this vaccine. PrEP and PEP regimens will be further improved to maximize uptake and reduce clinical symptoms, for example, reduced number of doses for IM PEP and condensed PEP ID regimens to 1 week. An abbreviated PrEP regimen schedule for Rabipur may become officially available.

Key issues
  • Rabies continues to cause high numbers of unnecessary human deaths in endemic countries, despite available rabies biologicals for prevention and treatment.

  • Children are at high risk for contracting rabies.

  • Rabipur is a cell-culture vaccine with long-lasting immunogenicity in different populations including children.

  • Rabipur efficacy in preventing rabies after exposure to the virus has been demonstrated in several clinical trials, and the vaccine showed a favorable tolerability and safety profile.

  • 30 years of clinical experience with Rabipur confirms the value of the vaccine in human rabies prophylaxis.

Acknowledgements

The authors wish to thank all of the many individuals who have participated in the clinical development of Rabipur over the past 30 years.

Financial & competing interests disclosure

The authors are employees of Novartis Vaccines. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. P Cates, of Apothecom, provided writing assistance that was paid for by Novartis Vaccines. K Jenks, N Tong, of Novartis Vaccines, provided editorial support. D Gniel was an employee of Novartis Vaccines and Diagnostics at the time of participation and writing of this manuscript.

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