827 EXPERIMENTAL HCV VACCINE COMBINING ADENOVIRUS AND PROTEIN ELICITS POTENT T-CELL RESPONSES AND NEUTRALIZING ANTIBODIES IN RODENTS

The SARS-CoV-2 pandemic introduced the world to a new type of vaccine based on mRNA encapsulated in lipid nanoparticles (LNPs). Instead of delivering antigenic proteins directly, an mRNA-based vaccine relies on the host’s cells to manufacture protein immunogens which, in turn, are targets for antibody and cytotoxic T cell responses. mRNA-based vaccines have been the subject of research for over three decades as a platform to protect against or treat a variety of cancers, amyloidosis and infectious diseases. In this review, we discuss mRNA-based approaches for the generation of prophylactic and therapeutic vaccines to HIV. We examine the special immunological hurdles for a vaccine to elicit broadly neutralizing antibodies and effective T cell responses to HIV. Lastly, we outline an mRNA-based HIV vaccination strategy based on the immunobiology of broadly neutralizing antibody development.

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Optimized Adenovirus-Antibody Complexes Stimulate Strong Cellular and Humoral Immune Responses against an Encoded Antigen in Naïve Mice and Those with Preexisting Immunity

Clinical and Vaccine Immunology ◽

10.1128/cvi.05319-11 ◽

2011 ◽

Vol 19 (1) ◽

pp. 84-95 ◽

Cited By ~ 6

Author(s):

Jin Huk Choi ◽

Joe Dekker ◽

Stephen C. Schafer ◽

Jobby John ◽

Craig E. Whitfill ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Immune Responses ◽

Neutralizing Antibodies ◽

T Cell Responses ◽

Transduction Efficiency ◽

Virus Antibody ◽

Cell Responses

ABSTRACTThe immune response to recombinant adenoviruses is the most significant impediment to their clinical use for immunization. We test the hypothesis that specific virus-antibody combinations dictate the type of immune response generated against the adenovirus and its transgene cassette under certain physiological conditions while minimizing vector-induced toxicity.In vitroandin vivoassays were used to characterize the transduction efficiency, the T and B cell responses to the encoded transgene, and the toxicity of 1 × 1011adenovirus particles mixed with different concentrations of neutralizing antibodies. Complexes formed at concentrations of 500 to 0.05 times the 50% neutralizing dose (ND50) elicited strong virus- and transgene-specific T cell responses. The 0.05-ND50formulation elicited measurable anti-transgene antibodies that were similar to those of virus alone (P= 0.07). This preparation also elicited very strong transgene-specific memory T cell responses (28.6 ± 5.2% proliferation versus 7.7 ± 1.4% for virus alone). Preexisting immunity significantly reduced all responses elicited by these formulations. Although lower concentrations (0.005 and 0.0005 ND50) of antibody did not improve cellular and humoral responses in naïve animals, they did promote strong cellular (0.005 ND50) and humoral (0.0005 ND50) responses in mice with preexisting immunity. Some virus-antibody complexes may improve the potency of adenovirus-based vaccines in naïve individuals, while others can sway the immune response in those with preexisting immunity. Additional studies with these and other virus-antibody ratios may be useful to predict and model the type of immune responses generated against a transgene in those with different levels of exposure to adenovirus.

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Induction of neutralizing antibodies and T cell responses by dengue virus type 2 envelope domain III encoded by plasmid and adenoviral vectors

Vaccine ◽

10.1016/j.vaccine.2006.06.031 ◽

2006 ◽

Vol 24 (42-43) ◽

pp. 6513-6525 ◽

Cited By ~ 33

Author(s):

Saima Khanam ◽

Navin Khanna ◽

Sathyamangalam Swaminathan

Keyword(s):

T Cell ◽

Dengue Virus ◽

Virus Type ◽

Neutralizing Antibodies ◽

T Cell Responses ◽

Adenoviral Vectors ◽

Cell Responses ◽

Domain Iii ◽

Dengue Virus Type 2

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CD8 T Cell Responses to an Immunodominant Epitope within the Nonstructural Protein NS1 Provide Wide Immunoprotection against Bluetongue Virus in IFNAR−/−Mice

Journal of Virology ◽

10.1128/jvi.00938-18 ◽

2018 ◽

Vol 92 (16) ◽

Cited By ~ 8

Author(s):

Alejandro Marín-López ◽

Eva Calvo-Pinilla ◽

Diego Barriales ◽

Gema Lorenzo ◽

Alejandro Brun ◽

...

Keyword(s):

T Cell ◽

Bluetongue Virus ◽

Neutralizing Antibodies ◽

Nonstructural Protein ◽

T Cell Responses ◽

Neutralizing Antibody ◽

Cd8 T Cell ◽

T Cell Response ◽

Cell Responses ◽

N Terminus

ABSTRACTThe development of vaccines against bluetongue, a prevalent livestock disease, has been focused on surface antigens that induce strong neutralizing antibody responses. Because of their antigenic variability, these vaccines are usually serotype restricted. We now show that a single highly conserved nonstructural protein, NS1, expressed in a modified vaccinia Ankara virus (MVA) vector can provide multiserotype protection in IFNAR−/−129 mice against bluetongue virus (BTV) that is largely dependent on CD8 T cell responses. We found that the protective antigenic capacity of NS1 resides within the N terminus of the protein and is provided in the absence of neutralizing antibodies. The protective CD8 T cell response requires the presence of a specific peptide within the N terminus of NS1, since its deletion ablates the efficacy of the vaccine formulation. These data reveal the importance of the nonstructural protein NS1 in CD8 T cell-mediated protection against multiple BTV serotypes when vectorized as a recombinant MVA vaccine.IMPORTANCEConventional vaccines have controlled or limited BTV expansion in the past, but they cannot address the need for cross-protection among serotypes and do not allow distinguishing between infected and vaccinated animals (DIVA strategy). There is a need to develop universal vaccines that induce effective protection against multiple BTV serotypes. In this work we have shown the importance of the nonstructural protein NS1, conserved among all the BTV serotypes, in CD8 T cell-mediated protection against multiple BTV serotypes when vectorized as a recombinant MVA vaccine.

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Immunogenicity and Cross-Reactivity of Rhesus Adenoviral Vectors

Journal of Virology ◽

10.1128/jvi.00159-18 ◽

2018 ◽

Vol 92 (11) ◽

Cited By ~ 2

Author(s):

M. Justin Iampietro ◽

Rafael A. Larocca ◽

Nicholas M. Provine ◽

Peter Abbink ◽

Zi Han Kang ◽

...

Keyword(s):

T Cell ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

T Cell Responses ◽

Adenoviral Vectors ◽

Cross Reactivity ◽

Human Populations ◽

Humoral Immune ◽

Cell Responses ◽

The Impact

ABSTRACT Adenovirus (Ad) vectors are being investigated as vaccine candidates, but baseline antivector immunity exists in human populations to both human Ad (HuAd) and chimpanzee Ad (ChAd) vectors. In this study, we investigated the immunogenicity and cross-reactivity of a panel of recently described rhesus adenoviral (RhAd) vectors. RhAd vectors elicited T cells with low exhaustion markers and robust anamnestic potential. Moreover, RhAd vector immunogenicity was unaffected by high levels of preexisting anti-HuAd immunity. Both HuAd/RhAd and RhAd/RhAd prime-boost vaccine regimens were highly immunogenic, despite a degree of cross-reactive neutralizing antibodies (NAbs) between phylogenetically related RhAd vectors. We observed extensive vector-specific cross-reactive CD4 T cell responses and more limited CD8 T cell responses between RhAd and HuAd vectors, but the impact of vector-specific cellular responses was far less than that of vector-specific NAbs. These data suggest the potential utility of RhAd vectors and define novel heterologous prime-boost strategies for vaccine development. IMPORTANCE To date, most adenoviral vectors developed for vaccination have been HuAds from species B, C, D, and E, and human populations display moderate to high levels of preexisting immunity. There is a clinical need for new adenoviral vectors that are not hindered by preexisting immunity. Moreover, the development of RhAd vector vaccines expands our ability to vaccinate against multiple pathogens in a population that may have received other HuAd or ChAd vectors. We evaluated the immunogenicity and cross-reactivity of RhAd vectors, which belong to the poorly described adenovirus species G. These vectors induced robust cellular and humoral immune responses and were not hampered by preexisting anti-HuAd vector immunity. Such properties make RhAd vectors attractive as potential vaccine vectors.

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HIV-1 Antibody Neutralization Breadth Is Associated with Enhanced HIV-Specific CD4+T Cell Responses

Journal of Virology ◽

10.1128/jvi.02278-15 ◽

2015 ◽

Vol 90 (5) ◽

pp. 2208-2220 ◽

Cited By ~ 22

Author(s):

Srinika Ranasinghe ◽

Damien Z. Soghoian ◽

Madelene Lindqvist ◽

Musie Ghebremichael ◽

Faith Donaghey ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Hiv Infection ◽

Neutralizing Antibodies ◽

T Cell Responses ◽

Neutralizing Antibody ◽

Antibody Activity ◽

Cell Responses

ABSTRACTAntigen-specific CD4+T helper cell responses have long been recognized to be a critical component of effective vaccine immunity. CD4+T cells are necessary to generate and maintain humoral immune responses by providing help to antigen-specific B cells for the production of antibodies. In HIV infection, CD4+T cells are thought to be necessary for the induction of Env-specific broadly neutralizing antibodies. However, few studies have investigated the role of HIV-specific CD4+T cells in association with HIV neutralizing antibody activity in vaccination or natural infection settings. Here, we conducted a comprehensive analysis of HIV-specific CD4+T cell responses in a cohort of 34 untreated HIV-infected controllers matched for viral load, with and without neutralizing antibody breadth to a panel of viral strains. Our results show that the breadth and magnitude of Gag-specific CD4+T cell responses were significantly higher in individuals with neutralizing antibodies than in those without neutralizing antibodies. The breadth of Gag-specific CD4+T cell responses was positively correlated with the breadth of neutralizing antibody activity. Furthermore, the breadth and magnitude of gp41-specific, but not gp120-specific, CD4+T cell responses were significantly elevated in individuals with neutralizing antibodies. Together, these data suggest that robust Gag-specific CD4+T cells and, to a lesser extent, gp41-specific CD4+T cells may provide important intermolecular help to Env-specific B cells that promote the generation or maintenance of Env-specific neutralizing antibodies.IMPORTANCEOne of the earliest discoveries related to CD4+T cell function was their provision of help to B cells in the development of antibody responses. Yet little is known about the role of CD4+T helper responses in the setting of HIV infection, and no studies to date have evaluated the impact of HIV-specific CD4+T cells on the generation of antibodies that can neutralize multiple different strains of HIV. Here, we addressed this question by analyzing HIV-specific CD4+T cell responses in untreated HIV-infected persons with and without neutralizing antibodies. Our results indicate that HIV-infected persons with neutralizing antibodies have significantly more robust CD4+T cell responses targeting Gag and gp41 proteins than individuals who lack neutralizing antibodies. These associations suggest that Gag- and gp41-specific CD4+T cell responses may provide robust help to B cells for the generation or maintenance of neutralizing antibodies in natural HIV-infection.

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Induction of Protective Cytotoxic T Cell Responses in the Presence of High Titers of Virus-neutralizing Antibodies: Implications for Passive and Active Immunization

Journal of Experimental Medicine ◽

10.1084/jem.187.4.649 ◽

1998 ◽

Vol 187 (4) ◽

pp. 649-654 ◽

Cited By ~ 36

Author(s):

Peter Seiler ◽

Marie-Anne Bründler ◽

Christine Zimmermann ◽

Doris Weibel ◽

Michael Bruns ◽

...

Keyword(s):

T Cell ◽

Neutralizing Antibodies ◽

T Cell Responses ◽

Lymphocytic Choriomeningitis ◽

Active Immunization ◽

Cytotoxic T Cell ◽

Protective Antibody ◽

Cell Responses ◽

Cell Immunity ◽

Cytotoxic T Cell Responses

The effect of preexistent virus-neutralizing antibodies on the active induction of antiviral T cell responses was studied in two model infections in mice. Against the noncytopathic lymphocytic choriomeningitis virus (LCMV), pretreatment with neutralizing antibodies conferred immediate protection against systemic virus spread and controlled the virus below detectable levels. However, presence of protective antibody serum titers did not impair induction of antiviral cytotoxic T lymphocyte (CTL) responses after infection with 102 PFU of LCMV. These CTLs efficiently protected mice independent of antibodies against challenge with LCMV–glycoprotein recombinant vaccinia virus; they also protected against otherwise lethal lymphocytic choriomeningitis caused by intracerebral challenge with LCMV-WE, whereas transfused antibodies alone did not protect, and in some cases even enhanced, lethal lymphocytic choriomeningitis. Against the cytopathic vesicular stomatitis virus (VSV), specific CTLs and Th cells were induced in the presence of high titers of VSV-neutralizing antibodies after infection with 106 PFU of VSV, but not at lower virus doses. Taken together, preexistent protective antibody titers controlled infection but did not impair induction of protective T cell immunity. This is particularly relevant for noncytopathic virus infections since both virus-neutralizing antibodies and CTLs are essential for continuous virus control. Therefore, to vaccinate against such viruses parallel or sequential passive and active immunization may be a suitable vaccination strategy to combine advantages of both virus-neutralizing antibodies and CTLs.

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Effects of neutralizing antibodies on escape from CD8 + T-cell responses in HIV-1 infection

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2014.0290 ◽

2015 ◽

Vol 370 (1675) ◽

pp. 20140290 ◽

Cited By ~ 6

Author(s):

Paul S. Wikramaratna ◽

José Lourenço ◽

Paul Klenerman ◽

Oliver G. Pybus ◽

Sunetra Gupta

Keyword(s):

T Cell ◽

Neutralizing Antibodies ◽

T Cell Responses ◽

Extended Period ◽

Antibody Responses ◽

Host Susceptibility ◽

Cell Responses ◽

Infection Dynamics ◽

Antibody Induction ◽

Hiv 1

Despite substantial advances in our knowledge of immune responses against HIV-1 and of its evolution within the host, it remains unclear why control of the virus eventually breaks down. Here, we present a new theoretical framework for the infection dynamics of HIV-1 that combines antibody and CD8 + T-cell responses, notably taking into account their different lifespans. Several apparent paradoxes in HIV pathogenesis and genetics of host susceptibility can be reconciled within this framework by assigning a crucial role to antibody responses in the control of viraemia. We argue that, although escape from or progressive loss of quality of CD8 + T-cell responses can accelerate disease progression, the underlying cause of the breakdown of virus control is the loss of antibody induction due to depletion of CD4 + T cells. Furthermore, strong antibody responses can prevent CD8 + T-cell escape from occurring for an extended period, even in the presence of highly efficacious CD8 + T-cell responses.

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