Accelerated Heterologous Adenovirus Prime-Boost SIV Vaccine in Neonatal Rhesus Monkeys

Liu, Jinyan; Li, Hualin; Iampietro, M. Justin; Barouch, Dan H.

doi:10.1128/jvi.00512-12

Cited by 11 publications

(6 citation statements)

References 44 publications

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“…Thus, our results demonstrate a profound Th1 bias of the immune response in both adult and neonatal mice after Ad26.RSV.preF immunization. These data are in line with previously published data on newborn rhesus monkeys showing that an Ad26 vectored vaccine induces CD4+ and CD8+ T cells producing IFN-γ when given on the day of birth 45 . Altogether this indicates that the Adenoviral vector platform is able to overcome the Th2 bias of the neonatal immune system, and instead induces Th1-biased responses.…”

Section: Discussionsupporting

confidence: 92%

Adenovector 26 encoded prefusion conformation stabilized RSV-F protein induces long-lasting Th1-biased immunity in neonatal mice

et al. 2020

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While RSV is a major cause of respiratory morbidity in infants, vaccine development is hindered by the immaturity and Th2-bias of the infant immune system and the legacy of enhanced respiratory disease (ERD) after RSV infection following immunization with formalin inactivated (FI)-RSV vaccine in earlier clinical trials. Preclinical studies have demonstrated that an adenoviral vector-based RSV F vaccine candidate (Ad26.RSV.FA2) induces Th1-biased protective immune responses, without signs of ERD upon subsequent RSV challenge. We here developed an Ad26 vector encoding the RSV F protein stabilized in its prefusion conformation (Ad26.RSV. preF). In adult mice, Ad26.RSV.preF induced superior, Th1-biased IgG2a-dominated humoral responses as compared to Ad26.RSV. FA2, while maintaining the strong Th1-biased cellular responses. Similar to adult mice, Ad26.RSV.preF induced robust and durable humoral immunity in neonatal mice, again characterized by IgG2a-dominated RSV F-binding antibodies, and high and stable virusneutralizing titers. In addition, vaccine-elicited cellular immune responses were durable and characterized by IFN-γ-producing CD4+ and CD8+ T cells, with a profound Th1 bias. In contrast, immunization of neonatal mice with FI-RSV resulted in IgG1 RSV F-binding antibodies associated with a Th2 phenotype, no detectable virus-neutralizing antibodies, and a Th2-biased cellular response. These results are supportive for the clinical development of Ad26.RSV.preF for use in infants.

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Section: Discussionsupporting

confidence: 92%

Adenovector 26 encoded prefusion conformation stabilized RSV-F protein induces long-lasting Th1-biased immunity in neonatal mice

et al. 2020

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“…Macaque CD45RO+ cells have high levels of the markers CD95 and CCR5, which are enriched on memory cells, the latter particularly in gut-associated tissues (Figures 4 and 8). In macaques, memory cells have been subdivided into subsets based on the expression of CD28, CD95, and CCR7, where CD95+ CCR7 - CD28+ defines transitional memory T cells (T TM ), CD95+ CCR7- CD28- defines effector memory (T EM ), and CD95+ CCR7+ CD28+ central memory (T CM ) [34]. In the PBMC and in the gut, the majority of CD45RO+ cells express both CD28 and CD95, and thus are either T CM or T TM .…”

Section: Discussionmentioning

confidence: 99%

Expression of the Memory Marker CD45RO on Helper T Cells in Macaques

et al. 2013

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BackgroundIn humans it has been reported that a major site of the latent reservoir of HIV is within CD4+ T cells expressing the memory marker CD45RO, defined by the mAb UCHL1. There are conflicting reports regarding the expression of this antigen in macaques, the most relevant animal species for studying HIV pathogenesis and testing new therapies. There is now a major effort to eradicate HIV reservoirs and cure the infection. One approach is to eliminate subsets of cells housing the latent reservoir, using UCHL1 to target these cells. So that such studies may be performed in macaques, it is essential to determine expression of CD45RO.MethodsWe have used immunofluorescence and flow cytometry to study cell surface expression of CD45RO on lymphocytes from PBMC, lymphoid, and GI organs of rhesus, pigtailed, and cynomolgus macaques. Both direct and indirect immunofluorescence experiments were performed.FindingsCD45RO is expressed on a subset of CD4+ lymphocytes of all pigtailed, a fraction of rhesus, and neither of the cynomolgus macaques studied. The binding of UCHL1 to macaque cells was of lower avidity than to human cells. This could be overcome by forming UCHL1 multimers. Directly conjugating fluors to UCHL1 can inhibit UCHL1 binding to macaque cells. Patterns of UCHL1 expression differ somewhat in macaques and humans, and from that of other memory markers often used in macaques.ConclusionsCD45RO, defined with mAb UCHL1, is well expressed on CD4+ cells in pigtailed macaques. Using tissues recovered from latently infected pigtailed macaques we are determining whether UCHL1, or other memory markers, can define the cellular locus of the reservoir. The low avidity of this interaction could limit the utility of UCHL1, in its conventional form, to eliminate cells in vivo and test this approach in macaque models of HIV infection.

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“…It is possible that this baby was inoculated parenterally with maternal cells instead of mucosally with virus, resulting in rapid viremia without a previremic eclipse phase of viral replication in mucosal and lymphoid tissues. The positive outcome in this baby might therefore have reflected the route of transmission, the lack of an eclipse phase in tissues, the very rapid initiation of ART, and/or the paucity of memory CD4+ T lymphocytes in the neonatal immune system 29 .…”

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confidence: 99%

Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys

Whitney

Hill

Sanisetty

et al. 2014

Nature

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499

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The viral reservoir represents a critical challenge facing HIV-1 eradication strategies1–5. However, it remains unclear when and where the viral reservoir is seeded during acute infection and the extent to which it is susceptible to early antiretroviral therapy (ART). Here we show that the viral reservoir is seeded very early following mucosal SIV infection of rhesus monkeys and prior to systemic viremia. We initiated suppressive ART in groups of monkeys on days 3, 7, 10, and 14 following intrarectal SIVmac251 infection. Treatment on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later timepoints. In addition, treatment on day 3 abrogated the induction of SIV-specific humoral and cellular immune responses. Nevertheless, following discontinuation of ART after 24 weeks of fully suppressive therapy, virus rebounded in all animals, although animals treated on day 3 exhibited a delayed viral rebound as compared with animals treated on days 7, 10 and 14. The time to viral rebound correlated with total viremia during acute infection and with proviral DNA at the time of ART discontinuation. These data demonstrate that the viral reservoir is seeded very early following intrarectal SIV infection of rhesus monkeys, during the “eclipse” phase, and prior to viremia. This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.

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Accelerated Heterologous Adenovirus Prime-Boost SIV Vaccine in Neonatal Rhesus Monkeys

Cited by 11 publications

References 44 publications

Adenovector 26 encoded prefusion conformation stabilized RSV-F protein induces long-lasting Th1-biased immunity in neonatal mice

Adenovector 26 encoded prefusion conformation stabilized RSV-F protein induces long-lasting Th1-biased immunity in neonatal mice

Expression of the Memory Marker CD45RO on Helper T Cells in Macaques

Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys

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