Global characteristics of the rabies biologics market in 2017.

In 2017, the World Health Organization, the World Organisation for Animal Health, the Food and Agriculture Organization of the United Nations and the Global Alliance for Rabies control developed a strategic plan to end human rabies deaths by 2030. A survey for manufacturing capacity and product characteristics of rabies biologics was conducted to inform this process. Twenty-three of 42 manufacturers, responded, giving a market capacity for 2017 of 90 million vials for human vaccines, 2.5 million vials for rabies immunoglobulins, 2 million vials for monoclonal antibodies and 181 million vials for dog vaccines. Production capacity could be increased by many manufacturers but was limited by country demand, lack of long-term planning and restricted market expansion. Should countries implement national rabies elimination programmes where biologic needs are forecasted and production lead times respected, manufacturers can meet future supply needs towards global elimination of human dog-mediated rabies deaths.

Introduction

Rabies is a zoonotic viral disease, primarily transmitted by dogs, causing an estimated 59,000 human deaths annually [1], [2]. Rabies is inevitably fatal once symptoms appear but preventable by vaccinating dogs, administering appropriate Post-Exposure Prophylaxis (PEP) and pre-exposure prophylaxis (PREP). Over 15 million people receive PEP treatments each year. Rabies represents an annual global burden of 8.6 billion USD [1], [2].

The World Health Organization (WHO), the World Organisation for Animal Health (OIE), the Food and Agriculture Organization of the United Nations (FAO) and the Global Alliance for Rabies Control (GARC) are United Against Rabies and have developed a country-centric strategic plan to achieve the global goal of zero human dog-mediated rabies deaths by 2030 [3].

As countries work towards universal coverage and increasingly prioritize and incorporate rabies into health systems, the demand for high-quality and optimally-priced rabies biologics will increase. In 2017, the WHO Strategic Advisory Group of Experts (SAGE) on Immunization approved updated recommendations for rabies immunization to include cost-effective and dose-sparing intradermal (ID) regimens, shortened intramuscular (IM) vaccination regimens, and local administration of RIG into the wound site only, for severe category-III exposures [4].

To improve access to high-quality human vaccines and immunoglobulins, and to match the OIE-led dog rabies vaccine bank, WHO is advocating for a human rabies vaccine bulk procurement facility or stockpile [5]. Concurrently, the Global Alliance for Vaccines Initiative (GAVI) is considering rabies in its 2018 Vaccine Investment Strategy [6], [7]. To inform the global plan, the global landscape of the rabies biologics market of vaccines and immunoglobulins (including monoclonal antibodies (mAbs)) were assessed.

Methods

Survey questionnaire

The survey included 11 questions (Figure S1) on (1) Market capacity: Manufacturing locations, manufacturing capacity between 2013 and 2017, expansion capabilities, and lead times; (2) Product characteristics: vial sizes, thermotolerance, pharmacology, and storage conditions. The survey was hosted on the Qualtrics website between 4th to 26th May 2017 and 42 manufacturers were contacted through manufacturer networks; the International Federation of Pharmaceutical Manufacturers (IFPMA), the Developing Country Vaccine Manufacturers Network (DCVMN), and the Health for Animals (H4A) global animal medicines association, or directly.

Data analysis

Data was collected anonymously and analyzed in aggregate. Conservative estimates were used for data ranges (e.g.: lower values for thermotolerance, production capacity and thermostability ranges; higher values for lead times). Units of time were standardized assuming 30.4 days/month. Where required, percentage, mean, and standard error of the mean (SEM) were calculated. Analysis used Microsoft Excel and Graphpad Prism 6.

Results

Respondent statistics and global manufacturing capacity of rabies biologics

The survey response rate was 55% (23/42) with, 13, 7 and 10 manufacturers producing HV, immunoglobulins (RIGs and mAbs) and AV, respectively. Six manufacturers produced more than one rabies biologic type (Fig. 1A). Most manufacturing sites were in South-East Asia (SEARO; 10 respondents) and Europe (EURO, 8 respondents) (Fig. 1B).

Fig. 1

Summary statistics of respondents of the rabies biologics market survey. (A) Depicts the number of manufacturers according to types of available products by category. (B) Depicts the number of manufacturing sites per WHO regions for rabies biologics. RIG is Rabies immunoglobulin and mAbs are monoclonal antibodies. Total number of respondents was 23.

Using the survey responses, the rabies biologics market capacity had increased by 28, 19 and 8% since 2013, with a 2017 capacity of 90, 2.5 and 181 million vials for HV, blood-derived RIGs and AV, respectively (Fig. 2A–C). Noticeably, RIG quantities were lower than HV. One mAb producer, new to the market in 2017, indicated an annual production of 2 million vials, which is 4-fold higher than the 2017 average for blood-derived RIGs (Fig. 2C). Market expansion was possible within 5 years for 8, 6, and 9 manufacturers with a mean potential increase of 65, 90 and 68% for HV, immunoglobulins (including mAbs) and AV, respectively (Fig. 2D). One manufacturer could expand its product portfolio into rabies immunoglobulins.

Fig. 2

Global manufacturing capacity, production and storage capabilities of rabies biologic manufacturers (A–C) Summary statistics related to the annual production of vials of (A) animal vaccines, (B) human vaccines and (C) blood-derived RIGs. Results on the left axis are expressed as box and whisker plots providing summary statistics with the median (central line), interquartile range (box), minimum/maximum values (whiskers) depicted, and “+“ giving the mean. For the right axis results are expressed as black circles for the aggregated total of all responses. (D) Depicts the potential future market expansion within the next 5 years, expressed as a percentage over the capacity for 2017. (E) Depicts manufacturing lead times in number of days. (F) Depicts the capacity to store rabies biologics at their facilities on behalf of purchasers, expressed on a log scale. (D–F) Statistics expressed as the mean and SEM of all responses. n is the number of respondents providing quantitative data for (A–F).

Production lead times ranged from 0 to 180, 30–420 and 42–400 days, respectively, for HV, Immunoglobulins and AV (Fig. 2E). Storage of rabies biologics was possible for 19 respondents. Mean storage quantities were 2.4, 0.35 and 21.1 million doses for HV, immunoglobulins and AV, respectively (Fig. 2F).

Using the survey data, 22.5 million patients could complete PEP; assuming a 4 visit with a 0.5/1 ml dose per visit IM regimen. With a 65% market expansion, a further 14.6 million PEP courses could be available. ID regimens with HV vial sharing increases this value by up to 5-fold, assuming 0.2 ml dose per visit. Global estimates, for 2015, indicate that 375 million dogs need to be vaccinated to achieve the 70% coverage for breaking transmission, yet only 130 million doses were used [8]. Assuming a constant global dog population since 2015, our reported global AV capacity and market expansion statistics of 181 million doses and 68%, 304 million dogs could be vaccinated, double previous estimates.

Biological characteristics and formulation of rabies vaccines and immunoglobulins

All HV were tissue culture-derived and lyophilized for reconstitution to 0.5 or 1 ml (Table 1). All required storage between 2 and 8 °C, while 69% had thermotolerance and retain potency after exposure to high temperatures (Table 1). Most HV were stable between 25 and 36 months. Eight products had thermochromic vial monitors to measure cumulative heat exposure that could impact potency [9]. Sixty-nine percent of HV were injectable through ID and IM. Three of 13 HV manufacturers produced WHO-prequalified (PQ) vaccines (Table 1). Most are produced using purified VERO cells, but primary hamster kidney cells, human diploid cells, chick embryo cells, duck embryo cells, baby hamster kidney cell and a PIKA/Toll-like receptor 3 vaccine are available [10].

Table 1

Pharmacological and product characteristics for rabies biologics.

	Route of administration (No. responses)					Shelf life (months)				Temperature (% positive responses)
	IM	IM; ID	IM; SC	SC	Oral	12	18	24	25–36	Storage 2–8 °C	Thermo-Tolerance
Human vaccines	4	9	1N/A	N/A	N/A	0	1	3	8	9 (100%)	69%
RIGs & mAbs	4	3	N/A	N/A	N/A	0	0	2	4	7 (100%)	57%
Animal vaccines	1	N/A	4	3	1	1	2	2	4	7 (87.5%)2	29%
	Formulation (No. & percentage responses)					Biological source material (No. responses)				Vol. per vial (ml)
	Liquid			Lyophilized		Cell line		Equine plasma	Human plasma	Mean ± SEM
Human vaccines	1 (8%)			12 (92%)		Cell-line derived, n = 13				0.69+/−0.07
RIGs & mAbs	6 (86%)			1 (14%)		2		2	3	3.13+/−1.13
Animal vaccines	9 (100%)			0		Cell-line derived, n = 9				1.02+/−0.09

All responses were aggregated and presented as the total number of responses per category. Percentages were calculated relative to the number of responses available, empty values were excluded. SEM is standard error of the mean.

N/A not applicable.

one respondent provided −20 °C.

Rabies immunoglobulins comprise human/equine blood-derived RIGs, and cell line-derived mAbs (3, 2 and 2 products, respectively). Most are liquid vials between 0.5 and 5 ml and stable at 2–8 °C for over 24 months (Table 1). One respondent could provide a vial monitor. Only 43% (n = 3/7) had products suitable for both ID and IM injection (Table 1).

All AV were cell culture-derived vaccines in 1 ml liquid doses. All but one product required storage at 2–8 °C and were stable for 36 months. Two products had thermotolerance. Vial monitors were available for 2 AV products. Most vaccines required parenteral administration by subcutaneous (SC) or IM injection. Oral administration using baits were also possible (Table 1).

Discussion

Results strongly suggest that a lack of demand for rabies biologics by countries is limiting market expansion as many survey participants indicated options to increase production over that for 2017. However, since the survey, one PQ manufacturer has halted production. Indeed, the number of HV PEP courses of 22.5 million is in the same order as the estimated 15 million exposures. Therefore, rabies biological availability is unlikely to jeopardize country’s efforts to eliminate dog-mediated rabies human deaths by 2030. Most manufacturing capacity is in SEARO/WPRO and EURO regions, with Chinese (WPRO) and Indian (SEARO) markets most likely highly represented. Given the similarity of many product characteristics, HV suitable for ID administration with longer shelf lives, thermotolerance and vial monitors will have the competitive advantage.

Updated national rabies elimination plans incorporating improved forecasting for rabies biologics for humans and animals will be crucial to progress towards zero human rabies deaths by 2030. Manufacturers, in addition to ensuring the sale of high-quality products, are encouraged to align to WHO’s current position and pursue registration in countries to include intradermal administration on their labels. Countries are also encouraged to implement cost and dose saving regimens even if it means off-label use for an interim period [4].

Only 2% of bite victims, who require it, receive RIG [11]. Equine RIG is more cost-effective than human RIG and new products with improved safety profiles are clinically equivalent to human RIG for virus neutralization providing an attractive option for health systems [4]. The volume per dose for blood-derived RIGs between manufacturers varied and is likely from differences in biological source, purification and concentration procedures. If mAbs are competitively priced and their effectiveness in preventing human rabies deaths established through post market surveillance, they will improve supply long-term due to their reproducible and scalable technology, allowing for product standardization [10]. As part of the 2018 SAGE recommendations for rabies and to increase the efficacy and breadth of virus neutralization, WHO promotes the development of products that contain at least 2 mAbs with distinct epitopes [4], [10].

Mass dog vaccination sustainably reduces human rabies risk, yet in endemic regions only 20% of dogs are vaccinated [12]. Although there is shortfall in the AV needed to achieve 70% global dog vaccination coverage, this is not likely to be an issue, as global dog vaccination rates will increase gradually as countries implement national rabies elimination plans collectively contributing to the Global Elimination Strategy.

For all rabies biologics, should finances be available, supply chain needs forecasted, and production lead times respected by countries, manufacturers can meet future supply needs for rabies elimination programmes. Per unit cost was not considered but is important for countries with limited health resources. Manufacturers are encouraged to apply for WHO-PQ status for their HV to facilitate purchase by procurement agencies and the creation of global rabies stockpiles. Engagement of national regulatory agencies and regional regulatory networks, under the guidance of WHO, is needed to facilitate the registration of high-quality rabies mAbs and blood-derived RIGs.

Data statement

The survey data is not available for publication to maintain anonymity and confidentiality of data provided by the rabies biologics manufacturers.

Declaration of competing interests

The authors declare no competing financial interests.

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.