Rhesus monkeys for a nonhuman primate model of cytomegalovirus infections

Itell, Hannah L.; Kaur, Amitinder; Deere, Jesse D.; Barry, Peter A.; Permar, Sallie R.

doi:10.1016/j.coviro.2017.08.005

Cited by 58 publications

(49 citation statements)

References 89 publications

(75 reference statements)

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“…Yet, congenital virus transmission can be modeled using both guinea pigs and nonhuman primate models [7,24]. In particular, rhesus macaques and their corresponding endogenous rhesus CMV (RhCMV) are a highlyrelevant model for understanding adult/fetal HCMV pathogenesis [25,26] and congenital infection [9,27], as the physiology/immunology of rhesus monkey pregnancy is highly analogous to humans [25], there is extensive protein homology between RhCMV and HCMV [28], and certain mechanisms of viral immune evasion are conserved between these viruses [29,30]. Previously, our group demonstrated that the depletion of CD4 + T cells followed by intravenous RhCMV inoculation of seronegative pregnant monkeys resulted in consistent RhCMV congenital infection and a high rate of fetal loss [24].…”

Section: Introductionmentioning

confidence: 99%

Intrahost cytomegalovirus population genetics following antibody pretreatment in a monkey model of congenital transmission

et al. 2020

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Human cytomegalovirus (HCMV) infection is the leading non-genetic cause of congenital birth defects worldwide. While several studies have addressed the genetic composition of viral populations in newborns diagnosed with HCMV, little is known regarding mother-tochild viral transmission dynamics and how therapeutic interventions may impact within-host viral populations. Here, we investigate how preexisting CMV-specific antibodies shape the maternal viral population and intrauterine virus transmission. Specifically, we characterize the genetic composition of CMV populations in a monkey model of congenital CMV infection to examine the effects of passively-infused hyperimmune globulin (HIG) on viral population genetics in both maternal and fetal compartments. In this study, 11 seronegative, pregnant monkeys were challenged with rhesus CMV (RhCMV), including a group pretreated with a standard potency HIG preparation (n = 3), a group pretreated with a high-neutralizing potency HIG preparation (n = 3), and an untreated control group (n = 5). Targeted amplicon deep sequencing of RhCMV glycoprotein B and L genes revealed that one of the three strains present in the viral inoculum (UCD52) dominated maternal and fetal viral populations. We identified minor haplotypes of this strain and characterized their dynamics. Many of the identified haplotypes were consistently detected at multiple timepoints within sampled maternal tissues, as well as across tissue compartments, indicating haplotype persistence over time and transmission between maternal compartments. However, haplotype numbers and diversity levels were not appreciably different between control, standard-potency, and high-potency pretreatment groups. We found that while the presence of maternal antibodies reduced viral load and congenital infection, it had no apparent impact on intrahost viral genetic diversity at the investigated loci. Interestingly, some minor haplotypes present in fetal and maternal-fetal interface tissues were also identified as minor haplotypes in

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Section: Introductionmentioning

confidence: 99%

Intrahost cytomegalovirus population genetics following antibody pretreatment in a monkey model of congenital transmission

et al. 2020

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“…HCMV preclinical vaccine development is hindered by the fact that small animal models poorly represent host-pathogen biology and mechanisms of disease pathogenesis [26, 27]. We chose to test immunogenicity in rabbits because we previously demonstrated that vaccination can elicit antibodies with both neutralizing and non-neutralizing in vitro functionality [17].…”

Section: Discussionmentioning

confidence: 99%

HCMV glycoprotein B nucleoside-modified mRNA vaccine elicits antibody responses with greater durability and breadth than MF59-adjuvanted gB protein immunization

Nelson

Jenks

Pardi

et al. 2019

Preprint

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2 3 4 HCMV glycoprotein B nucleoside-modified mRNA vaccine elicits antibody responses with 5 greater durability and breadth than MF59-adjuvanted gB protein immunization 6 7 Short Title: Immunogenicity of next-generation HCMV gB vaccines 8 9 Cody 22 23 Abstract WC: 300 (300 max) 24 Author summary WC: 188 (200 max) 25 Main Text WC: 3,177 26 Methods WC: 3,142 2 27 Abstract:28 A vaccine to prevent maternal acquisition of human cytomegalovirus (HCMV) during pregnancy 29 is a primary strategy to reduce the incidence of congenital disease. Similarly, vaccination of 30 transplant recipients against HCMV has been proposed to prevent transplant-associated HCMV 31 morbidity. The MF59-adjuvanted glycoprotein B protein subunit vaccine (gB/MF59) is the most 32 efficacious tested to-date for both indications. We previously identified that gB/MF59 vaccination 33 elicited poor neutralizing antibody responses and an immunodominant response against gB 34 antigenic domain 3 (AD-3). Thus, we sought to test novel gB vaccines to improve functional 35 antibody responses and reduce AD-3 immunodominance. Groups of juvenile New Zealand White 36 rabbits were administered 3 sequential doses of full-length gB protein with an MF59-like squalene 37 adjuvant (analogous to clinically-tested vaccine), gB ectodomain protein (lacking AD-3) with 38 squalene adjuvant, or lipid nanoparticle (LNP)-packaged nucleoside-modified mRNA encoding 39 full-length gB. The AD-3 immunodominant IgG response following human gB/MF59 vaccination 40 was closely mimicked in rabbits, with 78% of binding antibodies directed against this region in the 41 full-length gB protein group compared to 1% and 46% in the ectodomain and mRNA-LNP-42 vaccinated groups, respectively. All vaccines were highly immunogenic with similar kinetics and 43 comparable peak gB-binding and functional antibody responses. Although gB ectodomain subunit 44 vaccination reduced targeting of non-neutralizing epitope AD-3, it did not improve vaccine-elicited 45 neutralizing or non-neutralizing antibody functions. gB nucleoside-modified mRNA-LNP-46 immunized rabbits exhibited enhanced durability of IgG binding to soluble and cell membrane-47 associated gB protein as well as HCMV-neutralizing function. Furthermore, the gB mRNA-LNP 48 vaccine enhanced breadth of IgG binding responses against discrete gB peptide residues. Finally, 49 low-magnitude gB-specific T cell activity was observed in the full-length gB protein and mRNA-50 LNP vaccine groups, though not in ectodomain-vaccinated rabbits. Altogether, these data suggest 51 that the gB mRNA-LNP vaccine candidate, aiming to improve upon the partial efficacy of gB/MF59 52 vaccination, should be further evaluated in preclinical models. Author summary:54 Human cytomegalovirus (HCMV) is the most common infectious cause of infant birth defects, 55 resulting in permanent neurologic disability for one newborn child every hour in the United States.56 Furthermore, this virus causes significant morbidity and mortality in immune-suppressed 57 transplant recipients. Af...

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“…The strict tropism of HCMV to humans urged the study of homologous cytomegaloviruses (CMVs) in other animal species. There is vast literature regarding murine CMV (MCMV) and also several reports about rhesus monkey CMV (RhCMV) models (for a brief overview, see Table 1) [20][21][22][23][24][25][26][27][28]. This wealth of work contributes extensively to the understanding of basic aspects of the interactions between CMV and the host.…”

Section: Mouse Models Of Hcmv Infections and Human Immune Responsesmentioning

confidence: 99%

Modeling Human Cytomegalovirus in Humanized Mice for Vaccine Testing

2020

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Human cytomegalovirus (HCMV or HHV-5) is a globally spread pathogen with strictly human tropism that establishes a life-long persistence. After primary infection, high levels of long-term T and B cell responses are elicited, but the virus is not cleared. HCMV persists mainly in hematopoietic reservoirs, whereby occasional viral reactivation and spread are well controlled in immunocompetent hosts. However, when the immune system cannot control viral infections or reactivations, such as with newborns, patients with immune deficiencies, or immune-compromised patients after transplantations, the lytic outbursts can be severely debilitating or lethal. The development of vaccines for immunization of immune-compromised hosts has been challenging. Several vaccine candidates did not reach the potency expected in clinical trials and were not approved. Before anti-HCMV vaccines can be tested pre-clinically in immune-compromised hosts, reliable in vivo models recapitulating HCMV infection might accelerate their clinical translation. Therefore, immune-deficient mouse strains implanted with human cells and tissues and developing a human immune system (HIS) are being explored to test anti-HCMV vaccines. HIS-mice resemble immune-compromised hosts as they are equipped with antiviral human T and B cells, but the immune reactivity is overall low. Several groups have independently shown that HCMV infections and reactivations can be mirrored in HIS mice. However, these models and the analyses employed varied widely. The path forward is to improve human immune reconstitution and standardize the analyses of adaptive responses so that HIS models can be forthrightly used for testing novel generations of anti-HCMV vaccines in the preclinical pipeline.

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Rhesus monkeys for a nonhuman primate model of cytomegalovirus infections

Cited by 58 publications

References 89 publications

Intrahost cytomegalovirus population genetics following antibody pretreatment in a monkey model of congenital transmission

Intrahost cytomegalovirus population genetics following antibody pretreatment in a monkey model of congenital transmission

HCMV glycoprotein B nucleoside-modified mRNA vaccine elicits antibody responses with greater durability and breadth than MF59-adjuvanted gB protein immunization

Modeling Human Cytomegalovirus in Humanized Mice for Vaccine Testing

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