Rabies pre-exposure vaccination of children with purified chick embryo cell vaccine (PCECV)

Abstract

Human rabies, mainly transmitted by dog bites, remains a major public health problem in developing countries. In Asian countries, such as India or the Philippines, where large free-ranging dog populations exist, the human death toll stays high. Children under the age of 15 y are at particular risk, representing up to half of the dog bite victims. While pre-exposure prophylaxis (PrEP) is commonly used in travelers from developed countries visiting areas of high endemicity, rabies vaccination is rarely used in highly endemic countries in contrast to post-exposure prophylaxis (PEP).

Purified Chick Embryo Cell Vaccine (PCECV, Rabipur®/RabAvert®, Novartis Vaccines and Diagnostics) is approved for pre- and post-exposure prophylaxis, either by the intramuscular route, or—where registered—by the intradermal route of administration. In more than 25 y of use, PCECV has been widely used for PrEP in children. This review summarizes the pediatric pre-exposure clinical trials using PCECV. In total, PCECV has been administered to more than 1,200 children in clinical trials, from toddlers to those in elementary school, using intramuscular and intradermal schedules, demonstrating safety and immunogenicity.

PrEP as part of routine pediatric vaccination programs may have a major role to play in human rabies prevention. Extensive clinical experience with PCECV supports intramuscular and intradermal PrEP in children as one pillar of human rabies prevention in developing countries.

Keywords: :

• rabies
• vaccine
• pre-exposure prophylaxis
• children
• PCECV

Introduction

Rabies is a zoonotic viral disease, causing acute encephalitis, not only in a wide variety of mammalian species, but also in humans. It is endemic on every continent except Antarctica. The World Health Organization estimates the number of human rabies deaths to be in the range of 30,000–60,000 cases per year.¹ While in Europe and North America the number of human cases is low, the human death toll is highest in Asia and Africa, where canine rabies is highly endemic. In Asia, an estimated 30,000 annual deaths occur. The highest burden of disease is probably seen in India, where up to 20,000 people die of rabies every year.² Children in endemic areas are at particularly high risk, as they may have contact to stray or community owned animals while playing outside and may not be able to ward off aggressive animals as easily as an adult. Forty percent of all animal bite exposures are seen in children below the age of 15,^3-5 and a similar percentage of human rabies deaths is found in this age group.⁶ In Thailand, a survey by the Thai Red Cross Society revealed that up to 30% of all children will have been bitten by a dog by the age of 15.⁷

Rabies post-exposure prophylaxis (PEP) has been demonstrated to be highly efficacious when administered in a timely and appropriate manner, following WHO recommendations.^3,8 This includes local wound treatment with soap and water, vaccination with a cell culture rabies vaccine and—according to the category of exposure—the administration of rabies immune globulin (RIG). However, RIG is expensive and not always available, and is often not used despite being indicated, sometimes leading to PEP failures.^9,10 These PEP failures should not mistakenly be called “vaccine failures”. In addition to these cases lacking RIG administration, a high percentage of human deaths occur due to a significant delay in PEP or even no PEP at all. Unfortunately, in some local communities, patients consult traditional healers and ‘witch doctors’, who might use ‘alternative’ or ‘historic remedies’ such as applying powders, various pastes or introducing objects into the bite wound, prescribing herbal drugs, or just placing a curse upon the biting animal. A recent survey in India found that more than 10% of bite victims had applied chillies, salt, lime, turmeric and snuff powders, oil, paste of leaves, acid, ash given by a magician or copper coins.¹¹ Not surprisingly, all these so-called remedies are ineffective and led to rabies deaths. Very rarely, “real” PEP failures have been reported in a few cases where each step has been followed apparently according to recommendations.¹² Contributing factors can be the host (immune response), pathogen characteristics (virulence, genetic variations) and exposure type (e.g., facial bites close to the brain).

Every rabies death is a tragedy for the bereaved family members, especially as it could have been prevented by proper rabies prophylaxis. An alternative to PEP is pre-exposure prophylaxis (PrEP), which consists of three doses of vaccine given on days 0, 7, and 21 or 28. A person vaccinated with a full schedule of three doses can be regarded as immunized for several years, and in the case of an exposure, only needs two booster doses, thus eliminating the need for RIG and saving money. Another means of reducing cost is intradermal (ID) vaccination. By using small doses of 0.1 mL in countries where ID administration is registered, the content of a vial of vaccine can be split and used for several patients who present at anti-rabies clinics on the same day. In a number of Asian countries, including Thailand, India, Sri Lanka, and the Philippines, ID PEP is used commonly. Such ID PEP is safe and well-tolerated, immunogenic and efficacious.^13,14 If a sufficient number of patients are given PEP within 6 h after reconstituting a vial of vaccine, this route of administration can save up to 80% of vaccine costs, compared with IM administration, depending on which brand of vaccine is used.¹⁴ The ID route of administration however, is not limited to PEP. In addition, PrEP can also be administered via the ID route.

Rabies PrEP is commonly used for people when they are at occupational risk of exposure. For example, such risks exist for veterinarians and veterinary students, bat and wildlife handlers, hunters, and laboratory personnel handling rabies virus, either in the field of biomedical research, serology or vaccine production. In addition, a significant number of travelers from developed countries visiting highly endemic areas receive PrEP before starting their journey. Up to now, after millions of PrEP doses have been administered, there has only been a single documented case of PrEP failure, which occurred more than 30 y ago in a US Peace Corps volunteer (PCV), who received intradermal rabies vaccination.^15,16 With the exception of this one fatality, rabies PrEP has been used successfully over the last several decades. Wider PrEP use in endemic countries is an important option for human rabies control and elimination efforts in addition to PEP, education and animal control.

As children living in rabies endemic countries are at particular risk of being exposed, it is important to target this population. Modern cell culture rabies vaccines like human diploid cell vaccine (HDCV), purified Vero cell rabies vaccine (PVRV), purified duck embryo vaccine (PDEV) or purified chick embryo cell vaccine (PVRV) are licensed for PrEP and can be used in children. Good immunogenicity and favorable tolerability and safety have been demonstrated in clinical trials using HDCV,^17,18 PVRV^19-23 and PCECV. This review focuses on PCECV and summarizes the clinical data from relevant clinical PrEP trials using PCECV in children (as summarized in Table 1).

Table 1. Clinical trials with Novartis Vaccines’ PCECV in children

Study	Publication /Year	N^a,b	Route	Age^c	Results
1	Lumbiganon et al. 1989^24	24 (24)	IM	2–15 y	All children had VNA concentrations > 0.5 IU/mL on day 14, PCECV well tolerated
2	Pengsaa et al. 2009^25	177 (177)	IM/ID	12–18 mo	IM administration resulted in 3- to 5-fold higher titers than ID; After 1 y all VNA concentrations were > 0.5 IU/mL in IM groups; all subjects had anamnestic responses to booster doses. Both IM and the 3-dose ID regimens demonstrated long-lasting immunogenicity, with persistence of immunological memory. PCECV was well tolerated. PCECV and JEV administered concomitantly were immunogenic and safe and did not influence each other.
3	Kamoltham et al. 2007,^26 Kamoltham et al. 2011^27	703 (73^d/147^e) 703 (703)	ID	4–8 y	Robust immune responses were detected in all children by day 49. Up to 5 y after primary vaccination, anamnestic immune responses occurred after two ID booster doses. No serious adverse reactions were seen.
4	Shanbag et al. 2008^28	115 (115)	IM	3–12 y	All subjects developed adequate VNA concentrations by day 49; PCECV was well tolerated, regardless of the volume used for reconstitution
Additional supporting studies
5	Sampath et al. 2005^30	45 (39)	IM (PEP)	8 mo to 16 y	Adequate immune responses by day 14 were detected in all subjects, regardless of the grade of malnutrition.
6	Ogutu et al. 2009^31	191 (-)	IM	12–47 mo	Safety assessment only, PCECV was well tolerated.

^a subjects receiving PCECV; additional study arms with comparator vaccine not taken into consideration. ^bactually enrolled and available for safety analysis, per-protocol immunogenicity analysis in parentheses. ^cat the time when the primary vaccination series was administered. ^davailable for immunogenicity after primary vaccination. ^eavailable for immunogenicity after booster vaccination.

Study 1—PrEP in children age 2–15

One of the early studies, specifically looking at immunogenicity and safety of PCECV in children, was conducted in Bangkok, Thailand, during 1986/87.²⁴ Twenty-four children, 2 to 15 y of age, had contact to suspect rabid dogs, but did not qualify for PEP, as the contact was just touching or petting an animal, or licks on intact skin, i.e., no exposure or category 1 exposure, according to WHO classifications.⁸ The children were administered PCECV on days 0, 7, and 28, either as a full dose (group 1), or a second group only using half of the dose.²⁴ In both groups, all children had VNA concentrations > 0.5 IU/mL by day 14 (Geometric Mean Concentrations [GMC] 3.80 IU/mL and 3.88 IU/mL, in groups 1 and 2, respectively; range 1.86–11.80 and 1.48–8.57 IU/mL, respectively), and increasing with a peak on day 28 (GMC 11.20 IU/mL and 8.10 IU/mL, respectively). By Day 90, VNA concentrations had decreased, but still all children had VNA concentrations above the generally acceptable VNA level of 0.5 IU/mL (range 1.17–29.73 IU/mL, 1.17–5.90 IU/mL, in groups 1 and 2, respectively). Reactions after vaccination occurred in 9 cases. These included fever (5 cases), tenderness (2 cases) and maculopapular rash (2 cases). No serious adverse reactions were reported.

In summary, PCECV was demonstrated to be safe and immunogenic when given IM to children up to 15 y of age.

Study 2—PrEP in toddlers

In another study from Thailand, the immunogenicity and safety of PCECV was evaluated among toddlers 12 to 18 mo of age.²⁵ The vaccine was administered concomitantly with Japanese Encephalitis Vaccine, which in Thailand is part of the Expanded Program of Immunization (EPI) and given routinely in this age group. PCECV was administered intramuscularly (group 1; a full 1.0 mL dose administered on days 0, 7, and 28; n = 44) to a second group, half the IM dose (0.5 mL, administered on days 0, 7, and 28; n = 45); intradermally (group 3; three 0.1 mL doses administered ID on days 0, 7, and 28; n = 44); to a 4th group, two 0.1 mL doses administered ID on days 0 and 28 (n = 44); and group 5 (n = 23) served as a control group, which received JEV but no rabies vaccine. In all 4 groups receiving rabies vaccine, adequate rabies VNA concentrations (≥ 0.5 IU/mL) were achieved 3 weeks after the last dose on Day 28. The IM administration resulted in 3- to 5-fold higher titers than the ID administration. The JEV immunogenicity was not influenced by PCECV. No immediate adverse reactions occurred after vaccinations and both PCECV and JEV were well tolerated. A similar rate of systemic reactions was seen in the children who received JEV alone, without significant differences. One year after primary immunization, all children vaccinated with the IM schedule maintained adequate VNA concentrations, while 97% and 61% of children vaccinated with the 3-ID and 2-ID schedules had adequate values, respectively. One year after the primary vaccination, a single booster dose was administered according to the route of administration in the primary vaccination series (ID or full/half IM dose). After the booster dose, all children demonstrated an anamnestic immune response within 7 d, regardless of the pre-booster VNA concentration.

In summary, the study demonstrated that PCECV is immunogenic and safe in toddlers, given either IM or ID, and rabies PrEP is not influenced by JEV.

Study 3—PrEP in schoolchildren

More than 700 schoolchildren, 4 to 8 y of age, were vaccinated with a two- or three-dose ID regimen (on days 0 and 28 or 0, 7, and 28) and examined immunogenicity and safety after the primary vaccination series (in a subset of about 100 subjects), as well as after two (simulated) PEP booster doses on days 0 and 3 (as if an exposure had occurred), one, three or five years after the primary vaccination series (in all subjects).^26,27 After the primary vaccination, all subjects (30/30 = 100%) who received 3 doses of PCECV and 98% (42/43) of those who had received 2 doses had VNA concentrations ≥ 0.5 IU/mL on day 49, indicative of an adequate immune response.²⁶ Over the year(s), VNA concentrations dropped as expected, and 1, 3 or 5 y later only 35–46% (3 dose groups) and 7–12% (2 dose groups) had maintained adequate VNA concentrations.²⁷ However, when two booster doses were administered three days apart, all children had an anamnestic response, reaching VNA concentrations ≥ 0.5 IU/mL within one or two weeks, regardless of the time interval between primary vaccination and administration of booster doses. In this study for safety evaluation only unsolicited serious adverse events were recorded. No serious adverse event (AE) attributed to vaccine administration occurred during the study.

In summary, ID PrEP with PCECV was found to be immunogenic and safe in schoolchildren aged 4 to 8 y for primary vaccination, and 2 ID booster doses 1, 3 or 5 y later led to adequate and rapid anamnestic responses.

Study 4—PrEP in school-aged children

The safety and immunogenicity of rabies vaccine was examined when administered IM to 175 children 3 to 12 y of age.²⁸ Either PCECV or a purified Vero cell rabies vaccine (PVRV) was given on days 0, 7 and 28 reconstituted in different volumes (1mL or 0.5mL PCECV, group A or B, or 0.5mL PVRV, group C; per protocol population n = 57, 58, and 55, respectively). In all groups, the children developed VNA concentrations above 0.5 IU/mL by day 49. No serious adverse drug reactions were seen, and except for one child with severe headache after one of the vaccinations, all local and systemic reactions were mild to moderate, without statistically significant differences between the groups. The most common solicited local and systemic reaction was pain at the injection site. For all three groups combined, pain at the injection site was reported 17 times 30 min after vaccination (all mild), and 32 times after 24 h (31 mild and one moderate reaction). Other reactions were: one mild erythema in group A, one mild swelling of the arm in group C, 15 fever reactions (14 mild and 1 moderate reaction, 6 reactions in group A, 7 in group B, 2 in group C), 8 myalgia reactions (7 mild and 1 moderate reactions; 2, 4, and 2 in group A, B, and C, respectively), 9 headache reactions (7 mild, 1 moderate in group A, 1 severe in group B), 5 times malaise (3 mild, 2 moderate reactions, twice in group A, 3 times in group B), one mild irritability in group B, one mild allergic reaction in group C.

In summary, PrEP with PCECV was demonstrated to be safe and immunogenic in schoolchildren, regardless of the volume of the injected vaccine. There were no significant differences in immunogenicity or tolerability between PCECV and PVRV.

Additional supporting pediatric studies using PCECV

Study 5—Post-exposure prophylaxis in malnourished children

The immune response to some vaccines, including typhoid and BCG, has been demonstrated to be lower in malnourished children when compared with that of healthy children.²⁹ As many children living in rabies endemic countries may be affected by malnutrition, a study was conducted in malnourished children to evaluate the immunogenicity of PEP with PCECV, administered according to the Essen schedule on days 0, 3, 7, 14, and 28.³⁰ All children with protein energy malnutrition levels from grade I to IV (IAP classification, total n = 39) achieved adequate VNA concentrations by day 14 with a GMC of 15.28 IU/mL. Upon completion of the vaccination regimen on day 30, similar high VNA concentrations were demonstrated in all subjects (GMC 16.47 IU/mL). No serious AEs occurred. AEs that were reported were mild or moderate in severity and resolved within a few days.

In summary, malnutrition did not influence the immunogenicity of PCECV

Study 6—PCECV as a control group in malaria vaccine development

In a randomized controlled study in Western Kenya, investigating a new malaria vaccine candidate, the control group, consisting of 191 children 12–47 mo of age, received 3 doses PCECV, administered IM into the anterolateral aspect of the thigh.³¹ Vaccine doses were given on days 0, 29, and 57, i.e., one month apart. As the primary objective was to assess malaria vaccine efficacy, no rabies VNA serology was performed. However, for safety and tolerability evaluation, solicited local and systemic reactions, as well as unsolicited AEs, were assessed for up to 6 d after vaccination. The PCECV group had 8% local and 16% systemic reactions. Grade 3 AEs included 4 cases of fever (2%), 2 cases of loss of appetite (1%), and 1 case of irritability (1%). Five cases of malaria occurred in the PCECV group, in which one had a fatal outcome. No serious AE was attributed to vaccination, and PCECV was well tolerated.

In summary, PCECV has a favorable safety and tolerability profile in toddlers and young children up to 47 mo of age.

Discussion

For the majority of vaccine-preventable infectious diseases the concept of vaccination at an early age in healthy children is well-established. The basic vaccination programs against diphtheria, tetanus, pertussis have been implemented worldwide decades ago and have significantly reduced the burden of disease throughout the world. Today’s vaccination schedules include other diseases like Hib and hepatitis B, even in most of the developing countries. While for these diseases childhood vaccination is not debated, rabies PrEP is rarely considered. The reasons may be several. Past rabies vaccines derived from nerve tissue were reactogenic and often resulted in severe adverse reactions, and therefore were only used in PEP cases where the side effects had to be accepted, taking into account the fatal consequences of not administering the vaccine. However, modern cell culture vaccines like HDCV, PVRV, PDEV or PCECV are safe and well tolerated. Their reactogenicity profile is not different from other childhood vaccines. Vaccination of children could also be established for rabies, from a safety as well as immunogenicity point of view. The scientific mechanism behind the immune response is the same: The contact with inactivated pathogen (in the case of rabies: inactivated whole virus) leads to a T-cell mediated immune response, generating memory cells, which in case of contact to the causative organism (or a booster dose of vaccine) triggers an anamnestic response.

Until today there has only been a single documented case of PrEP failure in a US Peace Corps volunteer (PCV) in 1983.^15,16 The 23-y old female PCV was working in Kenya, where she was bitten by a puppy, approximately 6 mo after completing a 3-dose ID PrEP series with Human Diploid Cell Vaccine (HDCV). Sixty-nine days after the bite she developed symptoms of rabies. At that time, no rabies virus neutralizing antibodies (VNA) were detected in her serum, and a sero-survey in other PCVs who received ID PrEP with the same lot of vaccine showed that 82% had no detectable VNA titers. An investigation looking at possible reasons for the poor immune responses could not identify one single explanation and suggested multifactorial causes, including immunosuppression by anti-malarial treatment.¹⁵ Except for this single case, with presumably millions of rabies PrEP doses administered, PrEP has been uniformly demonstrated to be effective in rabies prevention.

Modern cell culture vaccines like HDCV, PCECV, PDEV and PVRV are licensed for PrEP in all age groups including children.

PrEP with PCECV in children has been safe, well-tolerated and immunogenic. In studies using PrEP in children, all children achieved adequate VNA concentrations by day 14, i.e., after receiving two doses of vaccines, even before the last dose of vaccine was received. Regardless of the route of administration (IM or ID), VNA concentrations reached levels above 0.5 IU/mL, which is regarded as an adequate immune response after vaccination. This was independent of the age when PrEP was administered. To date, no difference was seen in the immune response of toddlers, school-aged children or adolescents. Failures in reaching adequate VNA have not been reported in healthy individuals. The only documented cases of PrEP seroconversion failures have been observed in immunocompromised persons. For example, HIV-infected children did not respond well to IM PrEP with HDCV, where the immune response correlated with the CD4⁺ T-cell levels.³² In addition, a 6-y-old child in Thailand with severe HIV infection failed to respond to a 3-dose vaccination series with HDCV and when bitten by a dog, did not respond to a 4-site ID PEP regimen (double the usual dose) with a PVRV.³³ Hence, in cases of immune deficiency, the IM route of administration should be used for rabies prophylaxis (PrEP or PEP) and in the event of an exposure RIG should be administered, regardless of the category of exposure.

While HIV infection undoubtedly has led to failure of adequate immune responses, the question of protein malnutrition compromising the immune system and in consequence leading to failure of vaccination has been addressed as well in a clinical trial. Although in that study (study 5) PCECV was administered in a PEP regimen, the study demonstrated that the grade of malnutrition does not influence the immune response of rabies prophylaxis with PCECV.

To date, ID PrEP has been shown to be safe and immunogenic, and when a vaccine with a licensed volume of 1mL (e.g., HDCV or PCECV) is used, it is highly economical, as theoretically up to 10 intradermal doses can be obtained from one vial. Taking into consideration some wastage (usually up to 9 doses can be obtained from a 1 vial, if syringes with fixed needles and low dead volume space are used), a 1mL-vial of vaccine can theoretically provide enough doses for 3 children to complete a full PrEP vaccination series. It must be emphasized that the same vial should not be kept for one individual, as upon reconstitution it should be used within 6 h, due to concerns about contamination.

In case a previously vaccinated individual is exposed, PEP booster doses are recommended on days 0 and 3. Such individuals develop an anamnestic immune response due to activation of memory cells, which will lead to a more rapid and pronounced immune response, thereby eliminating the need for RIG. As RIG might not be readily available in developing countries, or might not be affordable, PrEP in children can be a means of reducing the need for RIG. This not only avoids risks associated with incomplete PEP by omission of RIG administration, but also reduces the cost of PEP. One study compared the cost of PrEP vs. PEP, and depending on which type of RIG was used, PrEP became cost-comparable at dog bite incidences of 7% or 3%, respectively.³⁴

In addition, even in circumstances where the cost of PrEP is perceived to be high for society or the individual, PrEP vaccination has the potential to save lives, as not every animal bite patient receives proper PEP without delay. The reasons for this are multiple. Awareness of parents and children on what needs to be done after a bite may be inadequate. Traditional methods, like applying chili paste to a bite wound, are common in several countries, especially in rural areas. The financial condition of the bite victim’s family may not permit for purchasing necessary medication, or lead to a delay in PEP, until money for medication is secured. In addition, there is the time, travel, and lost wages, to locate an anti-rabies vaccination center and take a child to the clinic, which may be hours away.

Another point to consider is documentation of vaccination. In case a previously immunized child is bitten, the physician in charge of bite management and rabies prophylaxis may only be comfortable to provide the two necessary booster doses, if he/she sees documented proof of previous rabies vaccination. If not, the child may be subjected to the full PEP procedure for unimmunized individuals. Therefore, it is important to provide proof of vaccination in an immunization record or booklet. Such documentation however, applies to all childhood vaccinations, and is common practice for pediatricians administering childhood vaccines as part of a national immunization calendar.

One question that arises is the age at which PrEP should be administered. This is discussed frequently among rabies experts, but without clear resolution. In our opinion, vaccination may be offered as soon as the risk exists, which usually increases once children begin to walk, explore actively their surroundings, and play outside. For this increased risk, toddlers may be the right age. The advantage of a toddler targeted program also lies in the fact that toddlers come for routine immunization as part of national immunization programs and therefore the full birth cohort can be reached. In Thailand for instance JEV is on the national EPI calendar and this may be an opportunity to reach the largest number of children possible. Therefore, one of the pediatric PrEP studies using PCECV was conducted in this age group with concomitant JEV administration, demonstrating that the vaccines do not interfere with each other. While at the time of the study, inactivated mouse brain derived JEV was available and used, today’s inactivated JEV, which is produced on Vero cells, has a better safety profile.³⁵ Once toddlers are missed, the next age to reach a cohort would be school-aged children. However by then, an exposure may already have occurred,⁵ and consequently a reduced number of cases prevented. From an individual’s perspective, PrEP can be given at any age. In countries where ID vaccination is not yet approved by regulatory authorities or at travel clinics which may be attended for visiting canine rabies endemic countries, the full IM dose can be administered, safely and effectively.

For large scale implementation of rabies PrEP one of the prerequisites is vaccine safety. In the past, before modern cell culture vaccines were available, only highly reactogenic vaccines like nerve tissue vaccine could be used. Clearly their reactogenicity did not allow the use in healthy individuals. Times, however, have changed. Cell culture vaccines are much less reactogenic than NTV. For PCECV, clinical trials have demonstrated a tolerability profile that is acceptable for use in PrEP in healthy children.

Currently, PrEP is not used on a large scale as part of the EPI in any country. The Indian Academy of Pediatrics lists rabies vaccination as recommended for certain high risk groups. However, it is up to parents to decide, and often lack of education as well as the individual financial situation, minimizes vaccination of those who are in most need. An excellent example, however, for the use of PrEP in children in vaccination campaigns is demonstrated in the Philippines. During 2007, the so-called “anti-rabies act” was introduced, and since then routine rabies PrEP is recommended for children aged 5–14 y in areas where there is high incidence of rabies exceeding 2.5 human rabies cases per million population.³⁶ This might be the incidence that could be an acceptable compromise for investment by society and the expected number of lives saved. However, introducing PrEP will not have an immediate effect. If not introduced in combination with a catch-up campaign that for instance would cover all children regardless of age, it may take years to reach an effect which significantly reduces the burden of deaths due to rabies.

When comparing PrEP with other means of rabies prevention, PrEP alone will not solve the problem. The circulation of rabies virus in the reservoir species populations needs to be addressed. Inappropriate massive culling, as performed in China during 2009 did not reduce the burden of disease, and was highly controversial.³⁷ In contrast, proper animal vaccination and sterilization programs have been utilized, but are not always successful, and are expensive. By comparison, ID PrEP, as part of a comprehensive ‘One Health’ program, could protect children for as little as 2 US$ (pure vaccine cost, assuming 0.3mL needed for vaccination of one individual, i.e., about a third of a 1mL vial of vaccine, which in a large scale campaign is assumed to be provided at less than 6 US$). The best approach is a holistic strategy, which includes education and awareness, responsible pet ownership and mandatory pet dog vaccination, as well as proper PEP and PrEP. Recently, in the Philippines such an intersectoral program has been proven to be successful.³⁸ In the end, only a reduction of human deaths will prove whether the rabies elimination campaign was successful. Significantly, PrEP, whether given at an individual level, or more importantly at a population health level as part of regular routine mass vaccination programs, has a major role to play in human rabies prevention. Clearly, PCECV, with its favorable immunogenicity and safety profile in addition to a cost-economic ID mode of administration, may be a suitable option for this purpose.

Acknowledgments

The authors thank the investigators of the studies for their commitment conducting the clinical trials and Dr Alexandra Giesen, Novartis Vaccines and Diagnostics, Global Medical Affairs, and Dr Charles E. Rupprecht, Global Alliance for Rabies Control, for critical review of the manuscript.

Conflict of interest

The authors are employees of Novartis Vaccines and Diagnostics, manufacturer of PCECV.