Atraumatic Oral Spray Immunization with Replication-Deficient Viral Vector Vaccines

ABSTRACT The development of needle-free vaccines is one of the recently defined “grand challenges in global health” (H. Varmus, R. Klausner, R. Klausner, R. Zerhouni, T. Acharya, A. S. Daar, and P. A. Singer, Science 302:398-399, 2003). To explore whether a natural pathway to the inductive site of the mucosa-associated lymphatic tissue could be exploited for atraumatic immunization purposes, replication-deficient viral vector vaccines were sprayed directly onto the tonsils of rhesus macaques. Tonsillar immunization with viral vector vaccines encoding simian immunodeficiency virus (SIV) antigens induced cellular and humoral immune responses. Viral RNA levels after a stringent SIV challenge were reduced, providing a level of protection similar to that observed after systemic immunization with the same vaccines. Thus, atraumatic oral spray immunization with replication-deficient vectors can overcome the epithelial barrier, deliver the vaccine antigen to the mucosa-associated lymphatic tissue, and avoid induction of tolerance, providing a novel approach to circumvent acceptability problems of syringe and needle vaccines for children and in developing countries.

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A Bivalent, Spherical Virus-Like Particle Vaccine Enhances Breadth of Immune Responses against Pathogenic Ebola Viruses in Rhesus Macaques

Journal of Virology ◽

10.1128/jvi.01884-19 ◽

2020 ◽

Vol 94 (9) ◽

Author(s):

Karnail Singh ◽

Bishal Marasini ◽

Xuemin Chen ◽

Lingmei Ding ◽

Jaang-Jiun Wang ◽

...

Keyword(s):

Immune Responses ◽

Neutralizing Antibodies ◽

Ebola Virus ◽

Vaccine Development ◽

Rhesus Macaques ◽

Pathogenic Species ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Novel Approach ◽

Virus Like Particle

ABSTRACT The 2013–2016 Ebola outbreak in West Africa led to accelerated efforts to develop vaccines against these highly virulent viruses. A live, recombinant vesicular stomatitis virus-based vaccine has been deployed in outbreak settings and appears highly effective. Vaccines based on replication-deficient adenovirus vectors either alone or in combination with a multivalent modified vaccinia Ankara (MVA) Ebola vaccine also appear promising and are progressing in clinical evaluation. However, the ability of current live vector-based approaches to protect against multiple pathogenic species of Ebola is not yet established, and eliciting durable responses may require additional booster vaccinations. Here, we report the development of a bivalent, spherical Ebola virus-like particle (VLP) vaccine that incorporates glycoproteins (GPs) from Zaire Ebola virus (EBOV) and Sudan Ebola virus (SUDV) and is designed to extend the breadth of immunity beyond EBOV. Immunization of rabbits with bivalent Ebola VLPs produced antibodies that neutralized all four pathogenic species of Ebola viruses and elicited antibody-dependent cell-mediated cytotoxicity (ADCC) responses against EBOV and SUDV. Vaccination of rhesus macaques with bivalent VLPs generated strong humoral immune responses, including high titers of binding, as well as neutralizing antibodies and ADCC responses. VLP vaccination led to a significant increase in the frequency of Ebola GP-specific CD4 and CD8 T cell responses. These results demonstrate that a novel bivalent Ebola VLP vaccine elicits strong humoral and cellular immune responses against pathogenic Ebola viruses and support further evaluation of this approach as a potential addition to Ebola vaccine development efforts. IMPORTANCE Ebola outbreaks result in significant morbidity and mortality in affected countries. Although several leading candidate Ebola vaccines have been developed and advanced in clinical testing, additional vaccine candidates may be needed to provide protection against different Ebola species and to extend the durability of protection. A novel approach demonstrated here is to express two genetically diverse glycoproteins on a spherical core, generating a vaccine that can broaden immune responses against known pathogenic Ebola viruses. This approach provides a new method to broaden and potentially extend protective immune responses against Ebola viruses.

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Acute Effects of Pathogenic Simian-Human Immunodeficiency Virus Challenge on Vaccine-Induced Cellular and Humoral Immune Responses to Gag in Rhesus Macaques

Journal of Virology ◽

10.1128/jvi.73.3.1853-1859.1999 ◽

1999 ◽

Vol 73 (3) ◽

pp. 1853-1859 ◽

Cited By ~ 17

Author(s):

Krista K. Steger ◽

Paul M. Waterman ◽

C. David Pauza

Keyword(s):

Human Immunodeficiency Virus ◽

Immune Responses ◽

Rhesus Macaques ◽

Serum Antibody ◽

Virus Challenge ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Immunodeficiency Virus ◽

Shiv Infection ◽

Antibody Levels

ABSTRACT Simian-human immunodeficiency virus (SHIV) infection in macaques provides a convenient model for testing vaccine efficacy and for understanding viral pathogenesis in AIDS. We immunized macaques with recombinant, Salmonella typhimurium (expressing Gag) or soluble Gag in adjuvant to generate T-cell-dependent lymphoproliferative or serum antibody responses. Immunized animals were challenged by intrarectal inoculation with SHIV89.6PD. Virus infection was accompanied by rapid losses of lymphoproliferative responses to Gag or phytohemagglutinin. By 8 weeks, mitogen responses recovered to near normal levels but antigen-specific immunity remained at low or undetectable levels. Serum antibody levels were elevated initially by virus exposure but soon dropped well below levels achieved by immunization. Our studies show a rapid depletion of preexisting Gag-specific CD4+ T cells that prevent or limit subsequent antiviral cellular and humoral immune responses during acute SHIV infection.

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Faculty Opinions recommendation of Comparative ability of plasmid IL-12 and IL-15 to enhance cellular and humoral immune responses elicited by a SIVgag plasmid DNA vaccine and alter disease progression following SHIV(89.6P) challenge in rhesus macaques.

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

10.3410/f.1079898.532828 ◽

2007 ◽

Author(s):

Michael Keefer

Keyword(s):

Immune Responses ◽

Disease Progression ◽

Dna Vaccine ◽

Plasmid Dna ◽

Rhesus Macaques ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Plasmid Dna Vaccine

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Induction of Humoral Immune Responses following Vaccination with Envelope-Containing, Formaldehyde-Treated, Thermally Inactivated Human Immunodeficiency Virus Type 1

Journal of Virology ◽

10.1128/jvi.79.8.4927-4935.2005 ◽

2005 ◽

Vol 79 (8) ◽

pp. 4927-4935 ◽

Cited By ~ 27

Author(s):

B. Poon ◽

J. T. Safrit ◽

H. McClure ◽

C. Kitchen ◽

J. F. Hsu ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Thermal Treatment ◽

Immune Responses ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The lack of success of subunit human immunodeficiency virus type 1 (HIV-1) vaccines to date suggests that multiple components or a complex virion structure may be required. We previously demonstrated retention of the major conformational epitopes of HIV-1 envelope following thermal treatment of virions. Moreover, antibody binding to some of these epitopes was significantly enhanced following thermal treatment. These included the neutralizing epitopes identified by monoclonal antibodies 1b12, 2G12, and 17b, some of which have been postulated to be partially occluded or cryptic in native virions. Based upon this finding, we hypothesized that a killed HIV vaccine could be derived to elicit protective humoral immune responses. Shedding of HIV-1 envelope has been described for some strains of HIV-1 and has been cited as one of the major impediments to developing an inactivated HIV-1 vaccine. In the present study, we demonstrate that treatment of virions with low-dose formaldehyde prior to thermal inactivation retains the association of viral envelope with virions. Moreover, mice and nonhuman primates vaccinated with formaldehyde-treated, thermally inactivated virions produce antibodies capable of neutralizing heterologous strains of HIV in peripheral blood mononuclear cell-, MAGI cell-, and U87-based infectivity assays. These data indicate that it is possible to create an immunogen by using formaldehyde-treated, thermally inactivated HIV-1 virions to induce neutralizing antibodies. These findings have broad implications for vaccine development.

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