Safety Assessment Studies in Nonhuman Primates

Worldwide regulatory guidelines for drug safety evaluations recommend testing in both a rodent and a nonrodent species. Non-human primates, which are phylogenetically close to man, are often thought of as the “ideal” nonrodent species. Historically, because of conservation issues, biosafety concerns, and price and supply issues, use of nonhuman primates in toxicology programs has been restricted to special cases. Recently, however, biopharmaceutical scientists have turned to primates as the only nonhuman species in which the biological activities of some drugs are expressed. Also, as the cost of test article for toxicology studies has increased, there has been a corresponding increase in the use of primates because of their smaller body size compared to dogs. With increasing demand, primatologists have solved the price, supply, and conservation issues by worldwide development of breeding centers that produce adequate numbers of well-characterized rhesus and cynomolgus macaques. New international personnel protective standards, shipping and quarantine requirements have addressed some of the public health concerns. However, tuberculosis, Herpesvirus simiae (B virus) and the “Ebola-like” hemorrhagic primate viruses remain of concern to primate researchers. With new requirements for specialized training, housing, equipment, and procedures for primate research and husbandry, many pharmaceutical companies now outsource their primate toxicology work to contract research organizations. The effort to “harmonize” international regulatory requirements for nonclinical toxicology has led to more uniformity in nonhuman primate study design. Typical study designs and procedures are discussed.

Molecular Evidence for Distinct Genotypes of Monkey B Virus (Herpesvirus Simiae) Which Are Related to the Macaque Host Species

ABSTRACT Although monkey B virus (herpesvirus simiae; BV) is common in all macaque species, fatal human infections appear to be associated with exposure to rhesus macaques (Macaca mulatta), suggesting that BV isolates from rhesus monkeys may be more lethal to nonmacaques than are BV strains indigenous to other macaque species. To determine if significant differences that would support this supposition exist among BV isolates, we compared multiple BV strains isolated from rhesus, cynomolgus, pigtail, and Japanese macaques. Antigenic analyses indicated that while the isolates were very closely related to one another, there are some antigenic determinants that are specific to BV isolates from different macaque species. Restriction enzyme digest patterns of viral DNA revealed marked similarities between rhesus and Japanese macaque isolates, while pigtail and cynomolgus macaque isolates had distinctive cleavage patterns. To further compare genetic diversity among BV isolates, DNA sequences from two regions of the viral genome containing genes that are conserved (UL27 and US6) and variable (US4 and US5) among primate alphaherpesviruses, as well as from two noncoding intergenic regions, were determined. From these sequence data and a phylogenetic analysis of them it was evident that while all isolates were closely related strains of BV, there were three distinct genotypes. The three BV genotypes were directly related to the macaque species of origin and were composed of (i) isolates from rhesus and Japanese macaques, (ii) cynomolgus monkey isolates, and (iii) isolates from pigtail macaques. This study demonstrates the existence of different BV genotypes which are related to the macaque host species and thus provides a molecular basis for the possible existence of BV isolates which vary in their levels of pathogenicity for nonmacaque species.