Two dimensional nanosheets as immunoregulator improve HIV vaccine efficacy

ABSTRACTExtensive studies have demonstrated that infant immune responses are distinct from those of adults. Despite these differences, infant immunization can elicit protective immune responses at levels comparable to or, in some cases, higher than adult immune responses to many vaccines. To date, only a few HIV vaccine candidates have been tested in infant populations, and none of them evaluated vaccine efficacy. Recent exciting studies showing that HIV-infected infants can develop broad neutralizing antibody responses and that some HIV vaccine regimens can elicit high levels of potentially protective antibodies in infants provide support for the development and testing of HIV vaccines in pediatric populations. In this review, we discuss the differences in adult and infant immune responses in the setting of HIV infection and vaccination.

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Mucosal immune stimulation with HSV-2 and polyICLC boosts control of viremia in SIVΔNef vaccinated rhesus macaques with breakthrough SIV infection

10.1101/2020.06.02.129494 ◽

2020 ◽

Author(s):

Meropi Aravantinou ◽

Olga Mizenina ◽

Thilo Brill ◽

Jessica Kenney ◽

Christine Timmons ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Lymph Nodes ◽

Immune Activation ◽

Vaccine Efficacy ◽

Cd4 T Cells ◽

Hiv Vaccine ◽

Live Attenuated Vaccine ◽

Siv Infection ◽

The Impact

ABSTRACTDevelopment of an effective human immunodeficiency virus (HIV) vaccine is among the highest priorities in the biomedical research agenda. Adjuvants enhance vaccine efficacy, but in the case of HIV, strong or inappropriate immune activation may undermine protection by increasing HIV susceptibility. Co-infection with immunomodulatory pathogens may also impact vaccine efficacy. In the rhesus macaque rectal SIVΔNef live attenuated vaccine model, we utilized a low virulence HSV-2 infection and the double-stranded RNA viral mimic polyICLC as tools to probe the effects of distinct types of immune activation on HIV vaccine efficacy and explore novel correlates of protection from wild type SIV. Rectally administered HSV-2 and polyICLC impacted the protection conferred by mucosal SIVΔNef vaccination by favoring partial protection in animals with breakthrough infection following virulent SIV challenge (“Controllers”). However, SIVΔNef persistence in blood and tissues did not predict protection in this rectal immunization and challenge model. Non-controllers had similar SIVΔNef viremia as completely protected macaques, and while they tended to have less replication competent SIVΔNef in lymph nodes, controllers had no recoverable virus in the lymph nodes. Non-controllers differed from protected macaques immunologically by having a greater frequency of pro-inflammatory CXCR3+CCR6+ CD4 T cells in blood and a monofunctional IFNγ-dominant CD8 T cell response in lymph nodes. Controller phenotype was associated with heightened IFNα production during acute SIV infection and a greater frequency of CXCR5+ CD4 T cells in blood pre-challenge despite a lower frequency of cells with the T follicular helper (Tfh) cell phenotype in blood and lymph nodes. Our results establish novel correlates of immunological control of SIV infection while reinforcing the potential importance of T cell functionality and location in SIVΔNef efficacy. Moreover, this work highlights that triggering of mucosal immunity can aid mucosal vaccine strategies rather than undermine protection.AUTHOR SUMMARYAn efficacious HIV vaccine is essential to contain the HIV pandemic. Vaccine-mediated protection from HIV may be either enhanced or obstructed by mucosal immune activation; thus, the impact of adjuvants and underlying co-infections that lead to immune activation needs to be evaluated. Using the SIV macaque model, we set out to study the impact of underlying infection with HSV-2 or treatment with the adjuvant polyICLC on rectal immunization with the live attenuated vaccine SIVΔNef. We found that neither stimulus impacted complete protection from SIV; however, the combination of HSV-2 and polyICLC improved control of infection in animals that were not completely protected. Compared with non-controller macaques, controllers had less inflammatory T cells before SIV challenge as well as greater gene expression of IFNα and more functional SIV-specific T cells after infection. The results add to our understanding of the mechanisms of SIVΔNef protection and demonstrate that mucosal immune activation does not necessarily undermine protection in mucosal vaccination against HIV.

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Rectal Acquisition of Simian Immunodeficiency Virus (SIV) SIVmac239 Infection despite Vaccine-Induced Immune Responses against the Entire SIV Proteome

Journal of Virology ◽

10.1128/jvi.00979-20 ◽

2020 ◽

Vol 94 (24) ◽

Author(s):

Mauricio A. Martins ◽

Lucas Gonzalez-Nieto ◽

Michael J. Ricciardi ◽

Varian K. Bailey ◽

Christine M. Dang ◽

...

Keyword(s):

T Cells ◽

Virus Infection ◽

Immune Responses ◽

Simian Immunodeficiency Virus ◽

Vaccine Efficacy ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Hiv Vaccine ◽

Partial Control ◽

Immunodeficiency Virus

ABSTRACT Given the complex biology of human immunodeficiency virus (HIV) and its remarkable capacity to evade host immune responses, HIV vaccine efficacy may benefit from the induction of both humoral and cellular immune responses of maximal breadth, potency, and longevity. Guided by this rationale, we set out to develop an immunization protocol aimed at maximizing the induction of anti-Envelope (anti-Env) antibodies and CD8+ T cells targeting non-Env epitopes in rhesus macaques (RMs). Our approach was to deliver the entire simian immunodeficiency virus (SIV) proteome by serial vaccinations. To that end, 12 RMs were vaccinated over 81 weeks with DNA, modified vaccinia Ankara (MVA), vesicular stomatitis virus (VSV), adenovirus type 5 (Ad5), rhesus monkey rhadinovirus (RRV), and DNA again. Both the RRV and the final DNA boosters delivered a near-full-length SIVmac239 genome capable of assembling noninfectious SIV particles and inducing T-cell responses against all nine SIV proteins. Compared to previous SIV vaccine trials, the present DNA-MVA-VSV-Ad5-RRV-DNA regimen resulted in comparable levels of Env-binding antibodies and SIV-specific CD8+ T-cells. Interestingly, one vaccinee developed low titers of neutralizing antibodies (NAbs) against SIVmac239, a tier 3 virus. Following repeated intrarectal marginal-dose challenges with SIVmac239, vaccinees were not protected from SIV acquisition but manifested partial control of viremia. Strikingly, the animal with the low-titer vaccine-induced anti-SIVmac239 NAb response acquired infection after the first SIVmac239 exposure. Collectively, these results highlight the difficulties in eliciting protective immunity against immunodeficiency virus infection. IMPORTANCE Our results are relevant to HIV vaccine development efforts because they suggest that increasing the number of booster immunizations or delivering additional viral antigens may not necessarily improve vaccine efficacy against immunodeficiency virus infection.

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Induction of Potent and Long-Lived Antibody and Cellular Immune Responses in the Genitorectal Mucosa Could be the Critical Determinant of HIV Vaccine Efficacy

Frontiers in Immunology ◽

10.3389/fimmu.2014.00202 ◽

2014 ◽

Vol 5 ◽

Cited By ~ 8

Author(s):

Nadia Chanzu ◽

Beatrice Ondondo

Keyword(s):

Immune Responses ◽

Vaccine Efficacy ◽

Hiv Vaccine ◽

Critical Determinant ◽

Cellular Immune Responses ◽

Cellular Immune

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Early cytokine and chemokine gene expression in lymph nodes of macaques infected with SIV is predictive of disease outcome and vaccine efficacy

Immunology Letters ◽

10.1016/s0165-2478(97)86952-0 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 30

Author(s):

W Zou

Keyword(s):

Gene Expression ◽

Lymph Nodes ◽

Vaccine Efficacy ◽

Disease Outcome ◽

Chemokine Gene ◽

Chemokine Gene Expression

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Systemic immune reaction in axillary lymph nodes adds to tumor-infiltrating lymphocytes in triple-negative breast cancer prognostication

npj Breast Cancer ◽

10.1038/s41523-021-00292-y ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Fangfang Liu ◽

Thomas Hardiman ◽

Kailiang Wu ◽

Jelmar Quist ◽

Patrycja Gazinska ◽

...

Keyword(s):

Breast Cancer ◽

Immune Responses ◽

Lymph Nodes ◽

Triple Negative ◽

Tumor Infiltrating Lymphocytes ◽

Axillary Lymph Nodes ◽

Axillary Lymph ◽

Her2 Positive ◽

Local Immunity ◽

Infiltrating Lymphocytes

AbstractThe level of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative (TNBC) and HER2-positive breast cancers convey prognostic information. The importance of systemic immunity to local immunity is unknown in breast cancer. We previously demonstrated that histological alterations in axillary lymph nodes (LNs) carry clinical relevance. Here, we capture local immune responses by scoring TILs at the primary tumor and systemic immune responses by recording the formation of secondary follicles, also known as germinal centers, in 2,857 cancer-free and involved axillary LNs on haematoxylin and eosin (H&E) stained sections from a retrospective cohort of 161 LN-positive triple-negative and HER2-positive breast cancer patients. Our data demonstrate that the number of germinal center formations across all cancer-free LNs, similar to high levels of TILs, is associated with a good prognosis in low TILs TNBC. This highlights the importance of assessing both primary and LN immune responses for prognostication and for future breast cancer research.

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Preparation for HIV Vaccine Efficacy Trials

Antibiotics and Chemotherapy - Development and Applications of Vaccines and Gene Therapy in AIDS ◽

10.1159/000425172 ◽

2015 ◽

pp. 155-160 ◽

Cited By ~ 1

Author(s):

Rodney Hoff ◽

Dale N. Lawrence

Keyword(s):

Vaccine Efficacy ◽

Hiv Vaccine ◽

Efficacy Trials

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Innate cell microenvironments in lymph nodes shape the generation of T cell responses during type I inflammation

Science Immunology ◽

10.1126/sciimmunol.abb9435 ◽

2021 ◽

Vol 6 (56) ◽

pp. eabb9435

Author(s):

Joseph M. Leal ◽

Jessica Y. Huang ◽

Karan Kohli ◽

Caleb Stoltzfus ◽

Miranda R. Lyons-Cohen ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Lymph Nodes ◽

Critical Role ◽

Myeloid Cell ◽

T Cell Responses ◽

Type I ◽

Cell Responses ◽

Inflammatory Monocytes ◽

Cell Effector

Microanatomical organization of innate immune cells within lymph nodes (LNs) is critical for the generation of adaptive responses. In particular, steady-state LN-resident dendritic cells (Res cDCs) are strategically localized to intercept lymph-draining antigens. Whether myeloid cell organization changes during inflammation and how that might affect the generation of immune responses are unknown. Here, we report that during type I, but not type II, inflammation after adjuvant immunization or viral infection, antigen-presenting Res cDCs undergo CCR7-dependent intranodal repositioning from the LN periphery into the T cell zone (TZ) to elicit T cell priming. Concurrently, inflammatory monocytes infiltrate the LNs via local blood vessels, enter the TZ, and cooperate with Res cDCs by providing polarizing cytokines to optimize T cell effector differentiation. Monocyte infiltration is nonuniform across LNs, generating distinct microenvironments with varied local innate cell composition. These spatial microdomains are associated with divergent early T cell effector programming, indicating that innate microenvironments within LNs play a critical role in regulating the quality and heterogeneity of T cell responses. Together, our findings reveal that dynamic modulation of innate cell microenvironments during type I inflammation leads to optimized generation of adaptive immune responses to vaccines and infections.

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