Viral Replication and Development of Specific Immunity in Macaques after Infection with Different Measles Virus Strains

Binnendijk, Robert S. van; Heijden, Roger W. J. van der; Amerongen, Geert van; Uytdehaag, Fons G. C. M.; Osterhaus, Albert D. M. E.

doi:10.1093/infdis/170.2.443

Cited by 104 publications

(133 citation statements)

References 12 publications

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“…Eight MeV-naive juvenile rhesus macaques (Table S1) were infected with the Bilthoven strain of WT MeV (20) by the respiratory route. After infection, all macaques developed a transient lymphopenia followed by a prolonged period of leukocytosis (Fig.…”

Section: Resultsmentioning

confidence: 99%

Prolonged persistence of measles virus RNA is characteristic of primary infection dynamics

Lin

Kouyos

Adams

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

109

136

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Measles virus (MeV) is the poster child for acute infection followed by lifelong immunity. However, recent work shows the presence of MeV RNA in multiple sites for up to 3 mo after infection in a proportion of infected children. Here, we use experimental infection of rhesus macaques to show that prolonged RNA presence is characteristic of primary infection. We found that viral RNA persisted in the blood, respiratory tract, or lymph nodes four to five times longer than the infectious virus and that the clearance of MeV RNA from blood happened in three phases: rapid decline coincident with clearance of infectious virus, a rebound phase with increases up to 10-fold, and a phase of slow decrease to undetectable levels. To examine the effect of individual host immune factors on MeV load dynamics further, we developed a mathematical model that expressed viral replication and elimination in terms of the strength of MeV-specific T-cell responses, antibody responses, target cell limitations, and immunosuppressive activity of regulatory T cells. Based on the model, we demonstrate that viral dynamics, although initially regulated by T cells, require antibody to eliminate viral RNA. These results have profound consequences for our view of acute viral infections, the development of prolonged immunity, and, potentially, viral evolution.immune responses | within-host modeling | virus clearance

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Section: Resultsmentioning

confidence: 99%

Prolonged persistence of measles virus RNA is characteristic of primary infection dynamics

Lin

Kouyos

Adams

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

109

136

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“…Old World primates usually develop a measles-like illness after challenge with wild-type MV but not after exposure to attenuated Edmonston vaccine strains. [31][32][33] Even "reactogenic" vaccines that cause a high frequency of measles-like illnesses in humans are innocuous in these animals. This may be because CD46 is expressed abundantly on macaque but not human red blood cells.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Pharmacology and Toxicology of Intravenous MV-NIS, an Oncolytic Measles Virus Administered With or Without Cyclophosphamide

et al. 2007

Clin Pharmacol Ther

113

125

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MV-NIS is an oncolytic measles virus encoding the human thyroidal sodium iodide symporter (NIS).Here, we report the results of preclinical pharmacology and toxicology studies conducted in support of our clinical protocol "Phase I Trial of Systemic Administration of Edmonston Strain of Measles Virus, Genetically Engineered to Express NIS, with or without Cyclophosphamide, in Patients with Recurrent or Refractory Multiple Myeloma." Dose-response studies in the KAS-6/1 myeloma xenograft model demonstrated a minimum effective dose of 4 × 10 6 TCID 50 (tissue culture infectious dose 50)/kg. Toxicity studies in measles-naive squirrel monkeys and measles-susceptible transgenic mice were negative at intravenous doses up to 10 8 and 4 × 10 8 TCID 50 /kg, respectively. Abundant viral mRNA, maximal on day 8, was detected in cheek swabs of squirrel monkeys, more so after pretreatment with cyclophosphamide. On the basis of these data, the safe starting dose of MV-NIS for our clinical protocol was set at 1 -2 × 10 4 TCID 50 /kg (10 6 TCID 50 per patient).Measles virus (MV, family Paramyxoviridae) was isolated in 1954 from the throat washings of a measles patient, David Edmonston. 1 Tissue culture passage resulted in loss of pathogenicity and attenuation of wild-type MV (Figure 1), giving rise to the Edmonston measles vaccines used worldwide today. 2 We recently discovered that attenuated Edmonston strain MV has potent antitumor activity in vitro and in vivo. 3 Intravenous, intratumoral, or intraperitoneal administration of the virus inhibited tumor growth or induced tumor regression in a variety of human tumor xenograft models. [4][5][6][7] To tailor the virus for cancer therapy, we Correspondence: SJ Russell (sjr@mayo.edu). CONFLICT OF INTERESTThe authors declared no conflict of interest. NIH Public Access Author ManuscriptClin Pharmacol Ther. Author manuscript; available in PMC 2009 October 28. Published in final edited form as:Clin Pharmacol Ther. 2007 December ; 82(6): 700-710. doi:10.1038/sj.clpt.6100409. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscripthave genetically engineered the viral coat protein to display tumor-targeting ligands to enable tumor-specific killing or inserted trackable transgenes into the viral genome to enable noninvasive monitoring of viral gene expression. [8][9][10][11][12] MV-NIS is an Edmonston-lineage MV that expresses the human sodium iodide symporter (hNIS) (Figure 2). 12 The NIS protein is normally expressed in the thyroid, mammary glands, stomach, and salivary tissue. Expression of NIS allows cells to actively transport iodide ions into the cell. Thus, patients with thyroid cancer are typically treated with 131 I to destroy the NIS-expressing thyroid cancer while leaving most normal tissues undamaged. 13 Loss of thyroid function due to the radiotherapy can be treated by replacement therapy with synthetic thyroid hormones. Insertion of NIS into MV facilitates pharmacokinetic evaluation and enhancement of MV oncolytic activity. MV-NIS-infected cells express...

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“…To determine whether respiratory immunization with MVDP would protect monkeys against wild-type MeV challenge, all vaccinated monkeys and three MeV-seronegative monkeys were challenged intratracheally with the Bilthoven wild-type strain of MeV14-16 mo after vaccination (28). Protection was assessed by presence or absence of rash and by measuring viremia and respiratory shedding of MeV.…”

Section: Quality Of the Mev-specific T-cell Responses To Mvdp Delivermentioning

confidence: 99%

Successful respiratory immunization with dry powder live-attenuated measles virus vaccine in rhesus macaques

Lin

Griffin

Rota³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Measles remains an important cause of childhood mortality worldwide. Sustained high vaccination coverage is the key to preventing measles deaths. Because measles vaccine is delivered by injection, hurdles to high coverage include the need for trained medical personnel and a cold chain, waste of vaccine in multidose vials and risks associated with needle use and disposal. Respiratory vaccine delivery could lower these barriers and facilitate sustained high coverage. We developed a novel single unit dose, dry powder live-attenuated measles vaccine (MVDP) for respiratory delivery without reconstitution. We tested the immunogenicity and protective efficacy in rhesus macaques of one dose of MVDP delivered either with a mask or directly intranasal with two dry powder inhalers, PuffHaler and BD Solovent. MVDP induced robust measles virus (MeV)-specific humoral and T-cell responses, without adverse effects, which completely protected the macaques from infection with wild-type MeV more than one year later. Respiratory delivery of MVDP was safe and effective and could aid in measles control.aerosol delivery | protective immunity | multifunctional T cells | antibody avidity M easles is a highly contagious viral disease. Before the availability of measles virus (MeV) vaccines, more than 130 million cases and 7-8 million deaths occurred annually. Intensive immunization efforts with the live attenuated measles vaccine (LAMV) given by injection have resulted in substantial decreases in global measles disease. However, with an estimated 164,000 deaths in 2008 (1), measles continues to be an important cause of child mortality, especially in less-developed regions of the world. The key to prevention of measles is achieving and sustaining high levels of population immunity through vaccination, and substantial challenges for high coverage remain in many countries. Some of the challenges to providing a first dose of measles vaccine to at least 95% of each birth cohort, plus a second dose to older children, are related to the method of vaccine delivery.Measles vaccine is given by injection, and this creates hurdles to sustained high coverage in many developing countries. First, there is often a shortage of the trained personnel needed for sterile reconstitution and safe injection of vaccine. Second, in most developing countries, lyophilized vaccine is in 5-10 dose vials that, after reconstitution, lose 30-50% potency in an hour at 37°C (2), so unused doses must be discarded. Third, contaminated needles and syringes create risks for transmitting bloodborne disease and require safe disposal.As a potential improvement, respiratory delivery of reconstituted liquid LAMV has been studied for more than three decades (3) but has never been licensed or widely used. Aerosol administration of aqueous vaccine is highly effective in boosting preexisting antibody and holds promise for use in older children (4-11), but primary humoral and cellular immune responses vary with the age of vaccinees (12-15).We have developed a dry powder formulation of ...

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Viral Replication and Development of Specific Immunity in Macaques after Infection with Different Measles Virus Strains

Cited by 104 publications

References 12 publications

Prolonged persistence of measles virus RNA is characteristic of primary infection dynamics

Prolonged persistence of measles virus RNA is characteristic of primary infection dynamics

Preclinical Pharmacology and Toxicology of Intravenous MV-NIS, an Oncolytic Measles Virus Administered With or Without Cyclophosphamide

Successful respiratory immunization with dry powder live-attenuated measles virus vaccine in rhesus macaques

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