Various injectable drugs for medical use based on immunoglobulin and their F(ab)2 fragments from horse blood plasma/serum are currently being developed and manufactured in the Russian Federation and abroad [1,2, – 3]:

–from especially hazardous viral diseases,

–from bacterial toxins,

–from snake and scorpion venoms.

The production and control of this blood plasma/serum and drug intermediates based on it should consider data on existing types of diseases in horses caused by viruses pathogenic for humans to minimize the risk of viral contamination. However, no such information in this area is given in the current State Pharmacopoeia of the Russian Federation, XIVth Ed. (SP RS XIV). Leading foreign regulators specify different numbers of viruses pathogenic for humans that cause diseases in horses. For example, recommendations of the European Medicines Agency (EMA) indicate 10 such diseases of 16 [4]; the Japanese Pharmacopoeia, 17th Ed. (JP 17), 7 [5].

Therefore, the aim of the present work was to use data from the domestic and foreign scientific literature to compile a list of viruses, including information on diseases that they cause in people. This information is necessary for manufacturers of equine immunoglobulin drugs:

–to choose animals (blood donors);

–to control horse blood plasma/serum and drug intermediates;

–to choose model viruses for work to assure viral drug safety.

For this, information on the following areas was selected using the modern scientific literature:

1) viral disease vectors in horses that are pathogenic and nonpathogenic for humans;

2) the distribution area of viral diseases in horses;

3) the incubation period and clinical presentation of viral diseases in horses including the percent deaths;

4) maximum virus concentrations in horse blood with viral diseases.

Table 1 presents the results of the investigations.

TABLE 1. List of Infectious Diseases in Horses Caused by Viruses Pathogenic and Nonpathogenic for Humans
Full size table

Table 1 shows the following:

36 viral diseases have been recorded worldwide in horses (instead of the 16 noted in the EMA materials [6]);

69% of viral diseases in horses (25 of 36) are caused by vectors pathogenic for people (instead of 10 and 7 noted in materials of the EMA [4] and JP 17 [5]);

52% of viral diseases of horses (13 of 25) that are caused by vectors pathogenic for people have distribution areas in Russia;

61% of all viral diseases of horses (22 of 36) have distribution areas in Russia;

many viral diseases of horses have mainly the same or a different clinical presentation, including death; however, they all can progress in an unapparent form (symptomless);

the maximum possible concentration of several viruses in horse blood reaches 8 log conventional units (CU)/mL with clearly pronounced clinical symptoms of the corresponding infection usually observed;

the incubation period of most equine viral diseases (not considering persistent infections) varies over a broad range, from 1 to 90 d but mainly up to 1 month.

Also, many researchers note in their publications that, as a rule, a frequently observed symptomless course of most viral diseases in horses occurs with lower peak virus blood concentrations than those noted in the table.

Therefore, horses (blood donors) for manufacturing of drugs based on specific immunoglobulins must be acquired from institutional farms safe for the 36 infectious diseases, especially paying attention to those vectors that are pathogenic for humans (25 noted in Table 1) and have distribution areas including Russia (13 viruses: Getah, Japanese encephalitis, West Nile fever, tick-borne encephalitis, rabies, equine herpesvirus types 1 – 4, equine influenza, encephalomyocarditis, foot-and-mouth disease, reovirus types 1 – 3, equine rotavirus, equine adenovirus, equine coronavirus). However, one of these pathogens, rabies, is not distributed in horses in Russia because all animals of this species in Russia are vaccinated against it. The manufacturer of the drugs should obtain from this farm the corresponding veterinarian certificates and quarantine the acquired horses (before starting immunization with the corresponding antigen) for one month (considering information of Rossel’khoznadzor regarding viral infections in horses [7]).

It is also noteworthy that all species of viruses causing disease in horses span a broad spectrum of families (17), of which 12 (Togaviridae, Flaviviridae, Rhabdoviridae, Herpesviridae, Paramyxoviridae, Orthomyxoviridae, Bornaviridae, Reoviridae, Poxviridae, Adenoviridae, Picornaviridae, Coronaviridae) contain equine viruses that are pathogenic for humans. Therefore, any viruses convenient for the researchers, a minimum of three virus species from these families belonging to three types, i.e., nonenveloped, enveloped RNA-containing, and enveloped DNA-containing (e.g., adenovirus, influenza virus, and vaccinia virus, respectively), can be used to choose model virus species required to validate technologies with different mechanisms of inactivation/elimination of viral contaminants in various materials during manufacturing of drugs based on horse blood. Studies to validate, e.g., two technologies with different mechanisms (physical, enzymatic, chemical, immunological, etc.) of inactivation/elimination of viral agents that are mentioned in pharmacopoeial requirements of leading global regulators [5, 62, 63] must reduce the infectious activity of the model viruses by at least 8 log units (100 million times). Considering the maximum possible accumulation level of several viruses in horse blood with the corresponding viral infections [8 log genetic copies (GC)/mL, Table 1], this degree of reduction of the infectious activity would practically exclude the presence of viable pathogen in the blood plasma/serum of this animal species. Moreover, if it is considered that horses with high virus blood concentrations would be immediately rejected because of their clearly pronounced clinical presentation of the disease.

Thus, modern domestic and foreign literature was used to compile the most complete list of viruses causing diseases in horses that included 36 viruses, 25 of which were pathogenic for humans and 13 of the 25 of which were pathogenic for humans and distributed in Russia. This list also contained information on the magnitude of incubation periods of the disease that are most often within one month; on the external clinical symptoms of these diseases that can also progress without symptoms; and on the maximum possible virus blood concentrations in horses with these diseases that can reach 8 log CU/mL of blood for individual infectious agents.

The analyzed data could be used at various manufacturing stages of equine immunoglobulin drugs for medical use in the following areas:

acquisition by drug manufacturers of horses (blood donors) from the corresponding institutional farms, paying attention to the presence/absence of viral diseases encountered among horses in Russia, especially those caused by viruses pathogenic for humans;

control of horse blood plasma/serum (for their possible rejection) during their quarantine (in the acquisition stage) to check for the presence/absence of viruses pathogenic for humans that are distributed in Russia;

control of pools of immune blood plasma/serum from immunized horses to check for the presence/absence of viruses pathogenic for humans encountered in Russia;

choice of model viruses from families in which disease vectors in horses that are pathogenic for humans are found to validate technologies for inactivation/elimination of the viruses used in the drug manufacturing process;

control of drug intermediates from the moment of filling the primary packaging to check for the presence/absence of viruses pathogenic for humans that are distributed in Russia.