Bishnu P Nayak

Novartis Vaccines, Cambridge, Massachusetts, United States

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Publications (3)25.52 Total impact

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    ABSTRACT: Adjuvants increase vaccine potency largely by activating innate immunity and promoting inflammation. Limiting the side effects of this inflammation is a major hurdle for adjuvant use in vaccines for humans. It has been difficult to improve on adjuvant safety because of a poor understanding of adjuvant mechanism and the empirical nature of adjuvant discovery and development historically. We describe new principles for the rational optimization of small-molecule immune potentiators (SMIPs) targeting Toll-like receptor 7 as adjuvants with a predicted increase in their therapeutic indices. Unlike traditional drugs, SMIP-based adjuvants need to have limited bioavailability and remain localized for optimal efficacy. These features also lead to temporally and spatially restricted inflammation that should decrease side effects. Through medicinal and formulation chemistry and extensive immunopharmacology, we show that in vivo potency can be increased with little to no systemic exposure, localized innate immune activation and short in vivo residence times of SMIP-based adjuvants. This work provides a systematic and generalizable approach to engineering small molecules for use as vaccine adjuvants. Copyright © 2014, American Association for the Advancement of Science.
    Science translational medicine 11/2014; 6(263):263ra160. DOI:10.1126/scitranslmed.3009980 · 15.84 Impact Factor
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    ABSTRACT: Background: Development of more effective therapies for genital herpes simplex virus type-2 (HSV-2) infections remains a priority. The toll-like receptors (TLR) are attractive targets for the immunomodulation of primary and recurrent genital herpes infection. The guinea pig model of genital HSV-2 disease was therefore used to evaluate the efficacy of a new TLR-7 agonist, SMIP-7.7. Methods: The effects of SMIP-7.7 at concentrations between 0.90% and 0.09% were compared to the vehicle control or Aldara(®) (3M Health Care Limited, Northridge, CA, USA) as treatment for genital HSV-2 infections. Following intravaginal inoculation of Hartley guinea pigs with 10(6) pfu HSV-2 (MS strain), animals were treated intravaginally beginning at 36 h post-infection. Animals were evaluated for acute disease, acute virus replication, recurrent disease and shedding, as well as infection of the dorsal root ganglia. Results: Treatment with SMIP-7.7 significantly decreased mean total lesion scores during primary infection (all doses, P<0.01 compared with vehicle control, and similar to Aldara(®)). Vaginal virus titres were reduced in treated animals compared with vehicle control (P<0.001 for each treatment versus vehicle control on day 4). Treatment with SMIP-7.7 also significantly decreased the number of recurrent lesion days, the number of days with recurrent virus shedding and the infection of the dorsal root ganglia compared to the vehicle control, and was similar to Aldara(®). As opposed to Aldara(®), SMIP-7.7 did not induce fever or weight loss during treatment. Conclusions: SMIP-7.7 improves the outcome of primary and recurrent HSV-2 disease comparable to Aldara(®) but without some of the side effects associated with Aldara(®).
    Antiviral chemistry & chemotherapy 12/2012; 23(5). DOI:10.3851/IMP2499
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    ABSTRACT: Fibroblastic reticular cells (FRCs) are lymphoid stromal cells essential to T-cell migration and survival. Although FRCs are targets of multiple viral infections, little is known about their role during infection due to the cells' scarcity and difficulty in isolating in vivo. To initiate studies of interactions among FRCs, viruses, and immune cells, we isolated and immortalized CD45(-)gp38(+)CD35(-)CD31(-)CD44(+)VCAM1(+) cell lines from C57BL/6 mice designated as immortalized FRC. Using these cloned cell lines, we have established that FRCs express the major histocompatibility complex (MHC) II molecule, a factor necessary for stimulation of CD4(+) T cells thought to be expressed primarily by antigen-presenting cells, along with other T-cell stimulatory ligands in an IFN-γ-dependent manner. In this environment, lymphocytic choriomeningitis virus (LCMV)-infected iFRCs activated naive LCMV-specific CD4(+) and CD8(+) T cells while limiting expansion of effector LCMV-specific T cells. Thus, FRCs effectively presented antigen along with activating signals during viral infection using both MHC I and MHC II molecules, illustrating a previously undescribed interaction with CD4(+) T cells and indicating a unique role for FRCs.
    Proceedings of the National Academy of Sciences 05/2012; 109(20):7823-8. DOI:10.1073/pnas.1205850109 · 9.67 Impact Factor