Deceptive imprinting and immune refocusing in vaccine design

Tobin, Gregory J.; Trujillo, Jessie D.; Bushnell, Ruth V.; Lin, George; Chaudhuri, Abhijit; Long, Jinxue; Barrera, José; Pena, Lindomar; Grubman, Marvin J.; Nara, Peter L.

doi:10.1016/j.vaccine.2008.09.080

Cited by 97 publications

(80 citation statements)

References 58 publications

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“…The feasibility of introducing additional sites for N-linked glycosylation to dampen the immunogenicity of specific antigenic regions of Env-based immunogens was demonstrated previously (14,16,36,37). However, the effect of such immunosilencing on the B cell response to other immunogenic regions within the same injected Env-based immunogens was not addressed in those studies.…”

Section: Discussionmentioning

confidence: 97%

“…HIV-1 Env has received considerable interest as a component of a prophylactic HIV-1 vaccine; however, Abs capable of neutralizing a broad array of circulating HIV-1 variants have not been induced by vaccination using current Env-based vaccine candidates (11)(12)(13). One proposed reason for this deficit is that B cell responses against the variable regions of HIV-1 Env dominate the response and, thereby, hamper the elicitation of more broadly reactive Env Abs to cross-conserved epitopes (14)(15)(16). That this is the case is unknown, but it is a central question for HIV-1 Env vaccine design.…”

Section: Njection With Recombinant Proteins In Adjuvant Generatesmentioning

confidence: 99%

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Independent Expansion of Epitope-Specific Plasma Cell Responses upon HIV-1 Envelope Glycoprotein Immunization

Forsell

Soldemo

Dosenovic

et al. 2013

The Journal of Immunology

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Abs that bind the functional envelope glycoprotein (Env) spike are considered critical for a broadly effective prophylactic HIV-1 vaccine. The difficulty in eliciting such Abs by vaccination is partially attributed to the immunodominance of hydrophilic, surface-exposed variable protein regions of Env. However, little is known about the potential for competition between B cells that recognize distinct and distal epitopes on Env during protein subunit vaccination. In this study, we address this basic question at the level of Ab-secreting cells and serum IgG using a pair of isogenic soluble Env trimers, designated wildtype and gV3, which differ only in their potential to activate B cell responses against the highly immunogenic V3 region of Env. Immunization of mice with gV3 resulted in a markedly lower Ag-specific response compared with that induced by wildtype Env and could be explained by a loss of V3-directed reactivities. There was no redistribution of the response to other regions of Env in gV3-inoculated mice, suggesting that the epitope-specific Ab-secreting cell responses measured after boost are independently regulated rather than dictated by direct or indirect competition between B cells recognizing different structural elements of Env. This information is relevant for ongoing efforts in Env immunogen design to focus responses on conserved neutralizing determinants and for our general understanding of B cell responses to large-protein Ags that display numerous B cell epitopes.

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Section: Discussionmentioning

confidence: 97%

Section: Njection With Recombinant Proteins In Adjuvant Generatesmentioning

confidence: 99%

Independent Expansion of Epitope-Specific Plasma Cell Responses upon HIV-1 Envelope Glycoprotein Immunization

Forsell

Soldemo

Dosenovic

et al. 2013

The Journal of Immunology

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“…One way of broadening the repertoire is through priming of immune responses to subdominant epitopes that are normally "silent" and not involved in the response during infection or primed by conventional immunization. Such a refocusing of the Ab response to subdominant epitopes has for viral pathogens been shown to result in a more broadly protective response (15,16). Thus, we hypothesized that a potential problem associated with current immunization strategies against a chronic disease such as TB is that they prime an immune response to epitopes that are already dominant T cell targets during the natural infection.…”

Section: Ycobacterium Tuberculosis (Mtb)mentioning

confidence: 99%

“…In addition to the immunodominant P1 (ESAT-6 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] ) epitope, the analysis of peptides covering the full sequence of ESAT-6 revealed two additional subdominant epitopes to which T cells are not primed during the natural infection. Immunization with both P3 (ESAT-6 [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] ) and P13 (ESAT-6 81-95 ) resulted in dose-dependent recall responses, demonstrating that it is possible to direct a specific response against other epitopes in the ESAT-6 molecule and that the ESAT-6 protein contains additional epitopes that can be processed and recognized by T cells. Interestingly, T cells directed to P3 (ESAT-6 15-29 ) did not recognize full-length ESAT-6 protein in vitro, indicating that this epitope is not naturally processed from the full-size ESAT-6 protein in vitro in the CB6F1 mouse strain.…”

Section: Identification Of Subdominant Epitopes In Esat-6mentioning

confidence: 99%

Quality and Vaccine Efficacy of CD4+ T Cell Responses Directed to Dominant and Subdominant Epitopes in ESAT-6 from Mycobacterium tuberculosis

Aagaard

Hoang²,

Vingsbo‐Lundberg³

et al. 2009

The Journal of Immunology

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The ESAT-6 (early secretory antigenic target) molecule is a very important target for T cell recognition during infection with Mycobacterium tuberculosis. Although ESAT-6 contains numerous potential T cell epitopes, the immune response during infection is often focused toward a few immunodominant epitopes. By immunization with individual overlapping synthetic peptides in cationic liposomes (cationic adjuvant formulation, CAF01) we demonstrate that the ESAT-6 molecule contains several subdominant epitopes that are not recognized in H-2d/b mice either during tuberculosis infection or after immunization with ESAT-6/CAF01. Immunization with a truncated ESAT-6 molecule (Δ15ESAT-6) that lacks the immunodominant ESAT-61–15 epitope refocuses the response to include T cells directed to these subdominant epitopes. After aerosol infection of immunized mice, T cells directed to both dominant (ESAT-6-immunized) and subdominant epitopes (Δ15ESAT-6-immunized) proliferate and are recruited to the lung. The vaccine-promoted response consists mainly of double- (TNF-α and IL-2) or triple-positive (IFN-γ, TNF-α, and IL-2) polyfunctional T cells. This polyfunctional quality of the CD4+ T cell response is maintained unchanged even during the later stages of infection, whereas the naturally occurring infection stimulates a response to the ESAT-61–15 epitope that consist almost exclusively of CD4+ effector T cells. ESAT-6 and Δ15ESAT-6 both give significant protection against aerosol challenge with tuberculosis, but the most efficient protection against pulmonary infection is mediated by the subdominant T cell repertoire primed by Δ15ESAT-6.

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“…[8][9][10][11] The development of vaccines against AVPs represents an unprecedented challenge. Researchers should pay close attention to many aspects of the mechanism of action of immune cells as well as to the complex and dynamic nature of the interaction between these cells and rapidly changing epitopes in APVs and cancer cells.…”

Section: Antigenically Variable Pathogensmentioning

confidence: 99%

Antigenic variability: Obstacles on the road to vaccines against traditionally difficult targets

Servín-Blanco

Zamora-Alvarado

Gevorkian

et al. 2016

Human Vaccines & Immunotherapeutics

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Despite the impressive impact of vaccines on public health, the success of vaccines targeting many important pathogens and cancers has to date been limited. The burden of infectious diseases today is mainly caused by antigenically variable pathogens (AVPs), which escape immune responses induced by prior infection or vaccination through changes in molecular structures recognized by antibodies or T cells. Extensive genetic and antigenic variability is the major obstacle for the development of new or improved vaccines against "difficult" targets. Alternative, qualitatively new approaches leading to the generation of disease-and patient-specific vaccine immunogens that incorporate complex permanently changing epitope landscapes of intended targets accompanied by appropriate immunomodulators are urgently needed. In this review, we highlight some of the most critical common issues related to the development of vaccines against many pathogens and cancers that escape protective immune responses owing to antigenic variation, and discuss recent efforts to overcome the obstacles by applying alternative approaches for the rational design of new types of immunogens.

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Deceptive imprinting and immune refocusing in vaccine design

Cited by 97 publications

References 58 publications

Independent Expansion of Epitope-Specific Plasma Cell Responses upon HIV-1 Envelope Glycoprotein Immunization

Independent Expansion of Epitope-Specific Plasma Cell Responses upon HIV-1 Envelope Glycoprotein Immunization

Quality and Vaccine Efficacy of CD4+ T Cell Responses Directed to Dominant and Subdominant Epitopes in ESAT-6 from Mycobacterium tuberculosis

Antigenic variability: Obstacles on the road to vaccines against traditionally difficult targets

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