Comparison of immunogenicity and safety outcomes of a malaria vaccine FMP013/ALFQ in rhesus macaques (Macaca mulatta) of Indian and Chinese origin

Abstract Background Indian-origin rhesus (InR) are preferred for research, but strict export restrictions continue to limit their use. Chinese-origin rhesus (ChR), although easier to procure, are genetically distinct from InR and differ in their immune response to infectious agents, such as the Simian Immunodeficiency Virus. The most advanced malaria vaccine, RTS,S (GlaxoSmithKline), is based on the circumsporozoite protein (CSP) of Plasmodium falciparum. The efficacy of RTS,S vaccine in the field remains low and short-lived; efforts are underway to improve CSP-based vaccines. Rhesus models can accelerate preclinical down-selection of the next generation of malaria vaccines. This study was used to determine if the safety and immunogenicity outcomes following vaccination with a CSP vaccine would differ in the InR and ChR models, given the genetic differences between the two sub-populations of rhesus. Methods The FMP013 vaccine, was composed of nearly full-length soluble P. falciparum CSP produced in Escherichia coli and was adjuvanted with the Army liposomal formulation (ALFQ). Three doses of the vaccine were administered in InR and ChR (n = 6) at 1-month intervals and the antibody and T cell responses were assessed. Results Local and systemic toxicity profile of FMP013 vaccine in InR and ChR were similar and they revealed that the FMP013 vaccine was safe and caused only mild and transient inflammatory adverse reactions. Following the first 2 vaccines, there was a slower acquisition of antibodies to the CSP repeat region in ChR. However after the 3rd vaccination the titers in the two models were comparable. The ChR group repeat-specific antibodies had higher avidity and ChR group showed higher inhibition of liver stage development activity compared to InR. There was no difference in T-cell responses to the FMP013 vaccine between the two models. Conclusions A difference in the quality of serological responses was detected between the two sub-populations of rhesus. However, both models confirmed that FMP013/ALFQ vaccine was safe, highly immunogenic, elicited functional antibodies and T-cell responses. Overall, the data suggests that rhesus of Indian and Chinese origins can be interchangeably used to compare the safety and immunogenicity of next-generation of malaria vaccines and adjuvants.

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Faculty Opinions recommendation of Durable protection of rhesus macaques immunized with a replicating adenovirus-SIV multigene prime/protein boost vaccine regimen against a second SIVmac251 rectal challenge: role of SIV-specific CD8+ T cell responses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1047136.498191 ◽

2006 ◽

Author(s):

Kendall Smith

Keyword(s):

T Cell ◽

Rhesus Macaques ◽

T Cell Responses ◽

Cd8 T Cell ◽

Vaccine Regimen ◽

Cell Responses ◽

Protein Boost ◽

Boost Vaccine

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Novel Recombinant Mycobacterium bovis BCG, Ovine Atadenovirus, and Modified Vaccinia Virus Ankara Vaccines Combine To Induce Robust Human Immunodeficiency Virus-Specific CD4 and CD8 T-Cell Responses in Rhesus Macaques

Journal of Virology ◽

10.1128/jvi.02607-09 ◽

2010 ◽

Vol 84 (12) ◽

pp. 5898-5908 ◽

Cited By ~ 19

Author(s):

Maximillian Rosario ◽

Richard Hopkins ◽

John Fulkerson ◽

Nicola Borthwick ◽

Máire F. Quigley ◽

...

Keyword(s):

T Cell ◽

Vaccinia Virus ◽

Mycobacterium Bovis ◽

Ex Vivo ◽

Rhesus Macaques ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses ◽

Modified Vaccinia Virus Ankara ◽

Hiv 1

ABSTRACT Mycobacterium bovis bacillus Calmette-Guérin (BCG), which elicits a degree of protective immunity against tuberculosis, is the most widely used vaccine in the world. Due to its persistence and immunogenicity, BCG has been proposed as a vector for vaccines against other infections, including HIV-1. BCG has a very good safety record, although it can cause disseminated disease in immunocompromised individuals. Here, we constructed a recombinant BCG vector expressing HIV-1 clade A-derived immunogen HIVA using the recently described safer and more immunogenic BCG strain AERAS-401 as the parental mycobacterium. Using routine ex vivo T-cell assays, BCG.HIVA401 as a stand-alone vaccine induced undetectable and weak CD8 T-cell responses in BALB/c mice and rhesus macaques, respectively. However, when BCG.HIVA401 was used as a priming component in heterologous vaccination regimens together with recombinant modified vaccinia virus Ankara-vectored MVA.HIVA and ovine atadenovirus-vectored OAdV.HIVA vaccines, robust HIV-1-specific T-cell responses were elicited. These high-frequency T-cell responses were broadly directed and capable of proliferation in response to recall antigen. Furthermore, multiple antigen-specific T-cell clonotypes were efficiently recruited into the memory pool. These desirable features are thought to be associated with good control of HIV-1 infection. In addition, strong and persistent T-cell responses specific for the BCG-derived purified protein derivative (PPD) antigen were induced. This work is the first demonstration of immunogenicity for two novel vaccine vectors and the corresponding candidate HIV-1 vaccines BCG.HIVA401 and OAdV.HIVA in nonhuman primates. These results strongly support their further exploration.

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CpG oligonucleotides induce strong humoral but only weak CD4+ T cell responses to protein antigens in rhesus macaques in vivo

Vaccine ◽

10.1016/j.vaccine.2005.01.077 ◽

2005 ◽

Vol 23 (25) ◽

pp. 3310-3317 ◽

Cited By ~ 20

Author(s):

Gunther Hartmann ◽

Anja Marschner ◽

Pablo Renner Viveros ◽

Christiane Stahl-Hennig ◽

Martin Eisenblätter ◽

...

Keyword(s):

T Cell ◽

Rhesus Macaques ◽

T Cell Responses ◽

Cd4 T Cell ◽

Protein Antigens ◽

Cell Responses ◽

Cpg Oligonucleotides

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Corrigendum to “MIG (CXCL9) is a more sensitive measure than IFN-γ of vaccine induced T-cell responses in volunteers receiving investigated malaria vaccines” [J. Immunol. Methods 340 (2009) 33–41]

Journal of Immunological Methods ◽

10.1016/j.jim.2011.03.002 ◽

2011 ◽

Vol 368 (1-2) ◽

pp. 84

Author(s):

Tamara K. Berthoud ◽

Susanna J. Dunachie ◽

Stephen Todryk ◽

Adrian V.S. Hill ◽

Helen A. Fletcher

Keyword(s):

T Cell ◽

T Cell Responses ◽

Sensitive Measure ◽

Cell Responses ◽

Malaria Vaccines ◽

Ifn Γ

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2729. mRNA Vaccines Encoding Conserved Influenza Antigens Induce Robust and Durable Immunity in Rhesus Macaques

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.2407 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S961-S961

Author(s):

Jessica Flynn ◽

Kara Cox ◽

Sinoeun Touch ◽

Yangsi Ou ◽

Teresa Weber ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Rhesus Macaques ◽

Vaccine Dose ◽

T Cell Responses ◽

Immune Recognition ◽

Serum Antibodies ◽

Ifn Gamma ◽

Cell Responses ◽

Lipid Nanoparticle

Abstract Background In response to immune pressure, influenza virus evolves, producing drifted variants capable of escaping immune recognition. One strategy for inducing a broad-spectrum immune response that can recognize multiple antigenically diverse strains is to target conserved proteins or protein domains. To that end, we assessed the immunogenicity of mRNA vaccines encoding the stem domain of hemagglutinin (HA) or nucleoprotein (NP) in nonhuman primates (NHPs). Methods Rhesus macaques were immunized three times intramuscularly, at 28 day intervals, with lipid nanoparticle-encapsulated mRNA encoding either HA stem (Yassine et al, 2015) or NP. Serum and PBMCs were collected up to 14 or 24 weeks, respectively, after the last vaccination. The magnitude and durability of humoral and cell-mediated immunity were evaluated. ELISA, competition ELISA, an in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) reporter bioassay, and microneutralization assays were used to characterize serum immune responses. Intracellular cytokine staining (IFN-gamma and IL-2) was used to assess antigen-specific T-cell responses. Results HA stem-immunized NHPs developed a robust anti-stem binding titer after a single vaccine dose, and after two doses, serum antibodies recognized several antigenically distinct Group 1 HA proteins. This broad antibody response persisted for at least 14 weeks post-dose 3 (PD3). Serum antibodies showed ADCC activity and competed with a well-characterized broadly neutralizing antibody, CR9114, for binding to HA stem; however, the polyclonal serum had only minimal activity against a panel of H1N1 viruses in a microneutralization assay. HA-specific CD4+ T-cell responses were detectable PD3. A robust antibody binding response was also detected in NP-vaccinated NHPs, and titers remained high for at least 14 weeks PD3. Additionally, these animals developed robust NP-specific T-cell responses that persisted for at least 24 weeks PD3. On average, 0.5% of CD4+ and 4% of CD8+ T cells produced IFN-gamma in response to NP peptide stimulation at the peak of the response, 2 weeks after the last vaccine dose was administered. Conclusion Lipid nanoparticle-encapsulated mRNA vaccines encoding conserved influenza antigens induce a robust and durable immune response in NHPs. Disclosures All authors: No reported disclosures.

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Sirolimus Enhances the Magnitude and Quality of Viral-Specific CD8+ T-Cell Responses to Vaccinia Virus Vaccination in Rhesus Macaques

American Journal of Transplantation ◽

10.1111/j.1600-6143.2010.03407.x ◽

2011 ◽

Vol 11 (3) ◽

pp. 613-618 ◽

Cited By ~ 76

Author(s):

A. P. Turner ◽

V. O. Shaffer ◽

K. Araki ◽

C. Martens ◽

P. L. Turner ◽

...

Keyword(s):

T Cell ◽

Vaccinia Virus ◽

Rhesus Macaques ◽

T Cell Responses ◽

Cd8 T Cell ◽

Virus Vaccination ◽

Cell Responses

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A chimeric protein-based malaria vaccine candidate induces robust T cell responses against Plasmodium vivax MSP119

Scientific Reports ◽

10.1038/srep34527 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 10

Author(s):

Jairo Andres Fonseca ◽

Monica Cabrera-Mora ◽

Balwan Singh ◽

Joseli Oliveira-Ferreira ◽

Josué da Costa Lima-Junior ◽

...

Keyword(s):

T Cell ◽

Plasmodium Vivax ◽

Malaria Vaccine ◽

Vaccine Candidate ◽

Chimeric Protein ◽

T Cell Responses ◽

Cell Responses ◽

Malaria Vaccine Candidate

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Optimization and qualification of an 8-color intracellular cytokine staining assay for quantifying T cell responses in rhesus macaques for pre-clinical vaccine studies

Journal of Immunological Methods ◽

10.1016/j.jim.2012.08.011 ◽

2012 ◽

Vol 386 (1-2) ◽

pp. 10-21 ◽

Cited By ~ 26

Author(s):

Mitzi M. Donaldson ◽

Shing-Fen Kao ◽

Leila Eslamizar ◽

Connie Gee ◽

Gerrit Koopman ◽

...

Keyword(s):

T Cell ◽

Rhesus Macaques ◽

Intracellular Cytokine Staining ◽

T Cell Responses ◽

Intracellular Cytokine ◽

Cell Responses

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Gamma Interferon-Mediated Inflammation Is Associated with Lack of Protection from Intravaginal Simian Immunodeficiency Virus SIVmac239 Challenge in Simian-Human Immunodeficiency Virus 89.6-Immunized Rhesus Macaques

Journal of Virology ◽

10.1128/jvi.78.2.841-854.2004 ◽

2004 ◽

Vol 78 (2) ◽

pp. 841-854 ◽

Cited By ~ 40

Author(s):

Kristina Abel ◽

Lisa La Franco-Scheuch ◽

Tracy Rourke ◽

Zhong-Min Ma ◽

Veronique de Silva ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Rhesus Macaques ◽

T Cell Responses ◽

Lymphoid Tissues ◽

Mrna Levels ◽

Cell Responses ◽

Immunodeficiency Virus ◽

Ifn Γ

ABSTRACT Although gamma interferon (IFN-γ) is a key mediator of antiviral defenses, it is also a mediator of inflammation. As inflammation can drive lentiviral replication, we sought to determine the relationship between IFN-γ-related host immune responses and challenge virus replication in lymphoid tissues of simian-human immunodeficiency virus 89.6 (SHIV89.6)-vaccinated and unvaccinated rhesus macaques 6 months after challenge with simian immunodeficiency virus SIVmac239. Vaccinated-protected monkeys had low tissue viral RNA (vRNA) levels, vaccinated-unprotected animals had moderate tissue vRNA levels, and unvaccinated animals had high tissue vRNA levels. The long-term challenge outcome in vaccinated monkeys was correlated with the relative balance between SIV-specific IFN-γ T-cell responses and nonspecific IFN-γ-driven inflammation. Vaccinated-protected monkeys had slightly increased tissue IFN-γ mRNA levels and a high frequency of IFN-γ-secreting T cells responding to in vitro SIVgag peptide stimulation; thus, it is likely that they could develop effective anti-SIV cytotoxic T lymphocytes in vivo. In contrast, both high tissue IFN-γ mRNA levels and strong in vitro SIV-specific IFN-γ T-cell responses were detected in lymphoid tissues of vaccinated-unprotected monkeys. Unvaccinated monkeys had increased tissue IFN-γ mRNA levels but weak in vitro anti-SIV IFN-γ T-cell responses. In addition, in lymphoid tissues of vaccinated-unprotected and unvaccinated monkeys, the increased IFN-γ mRNA levels were associated with increased Mig/CXCL9, IP-10/CXCL10, and CXCR3 mRNA levels, suggesting that increased Mig/CXCL9 and IP-10/CXCL10 expression resulted in recruitment of CXCR3+ activated T cells. Thus, IFN-γ-driven inflammation promotes SIV replication in vaccinated-unprotected and unvaccinated monkeys. Unlike all unvaccinated monkeys, most monkeys vaccinated with SHIV89.6 did not develop IFN-γ-driven inflammation, but they did develop effective antiviral CD8+-T-cell responses.

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