Clinical and Immunological Metrics During Pediatric Rhesus Macaque Development

Abstract

Background: Clinical measurements commonly used to evaluate overall health of laboratory animals including complete blood count, serum chemistry, weight, and immunophenotyping, differ with respect to age, development, and environment. This report provides comprehensive clinical and immunological reference ranges for pediatric rhesus macaques over the first year of life. Methods: We collected and analyzed blood samples from 151 healthy rhesus macaques, aged 0-55 weeks, and compared mother-reared infants to two categories of nursery-reared infants; those on an active research protocol and those under derivation for the expanded specific-pathogen-free breeding colony. Hematology was performed on EDTA-anticoagulated blood using a Sysmex XT2000i, and serum clinical chemistry was performed using the Beckman AU480 chemistry analyzer. Immunophenotyping of whole blood was performed with immunofluorescence staining and subsequent flow cytometric analysis on a BD LSRFortessa. Plasma cytokine analysis was performed using a Millipore multiplex Luminex assay. Results: For hematological and chemistry measurements, pediatric reference ranges deviate largely from adults. Comparison of mother-reared and nursery-reared animals revealed that large differences depend on rearing conditions and diet. Significant differences found between two nursery-reared cohorts (research and colony animals) indicate large influences of experimental factors and anesthetic events on these parameters. Immune cells and cytokine responses presented with distinct patterns for infants depending on age, birth location, and rearing conditions. Conclusions: Our results illustrate how the immune system changed over time and that there was variability among pediatric age groups. Reference ranges of results reported here will support interpretations for how infection and treatment may skew common immune correlates used for assessment of pathology or protection in research studies as well as help veterinarians in the clinical care of infant non-human primates. We highlighted Merino et al. Clinical Immunology of Infant Macaques the importance of using age-specific reference comparisons for pediatric studies and reiterated the utility of rhesus macaques as a model for human studies. Given the rapid transformation that occurs in multiple tissue compartments after birth and cumulative exposures to antigens as individuals grow, a better understanding of immunological development and how this relates to timing of infection or vaccination will support optimal experimental designs for developing vaccines and treatment interventions.

A Case Study to Dissect Immunity to SARS-CoV-2 in a Neonate Nonhuman Primate Model

“…After infection, the neonate exhibited asymptomatic clinical signs and had no major changes in temperature, oxygen saturation, respiratory rate, and heart rate ( Supplementary Figure S1A ). The newborn weighed around 450 g at birth and gained weight throughout the study, consistent with expected standards ( 45 ) ( Supplementary Figure S1B ).…”

Predictive Markers of Immunogenicity and Efficacy for Human Vaccines

“…Although systems vaccinology approaches have already been used in human cohorts of aged individuals [63,221,222], high-throughput characterization of vaccine-induced responses in children are still rare [9,223] and awaited for newborns [224]. Importantly, NHPs provide a highly relevant pediatric model to test vaccine efficacy, as they share many similarities with humans in terms of immune system development [225][226][227][228].…”

Hematological and biochemical reference intervals of wild-caught and inhouse adult Indian rhesus macaques (Macaca mulatta)

“…It is known that these reference values are affected by various parameters such as age, sex, fasting, sedation, or methods of restraint [3]. Some studies have either reported data of purpose-bred or wild-caught animals of different species [9,10]. However, no reports are available that compare and analyze reference values for hematological and biochemical parameters in inhouse and wild-sourced Indian rhesus monkeys.…”