How Can Vaccines Against Influenza and Other Viral Diseases Be Made More Effective?

Nara, Peter L.; Tobin, Gregory J.; Chaudhuri, Abhijit; Trujillo, Jessie D.; Lin, George; Cho, Michael W.; Levin, Simon A.; Ndifon, Wilfred; Wingreen, Ned S.

doi:10.1371/journal.pbio.1000571

Cited by 25 publications

(19 citation statements)

References 17 publications

(32 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such competition results in the immune system preferentially using memory cells in responding to the presentation of an immunogen immunoreactive with the memory B-cell receptors (33). Besides providing a rapid secondary immune response to reinfections with same pathogen, this mechanism is the basis for the phenomenon of original antigenic sin (OAS) (48), also known as heterologous immunity (49) or repertoire freeze (50).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Antigenic cooperation among intrahost HCV variants organized into a complex network of cross-immunoreactivity

Skums

Bunimovich

Khudyakov

2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Hepatitis C virus (HCV) has the propensity to cause chronic infection. Continuous immune escape has been proposed as a mechanism of intrahost viral evolution contributing to HCV persistence. Although the pronounced genetic diversity of intrahost HCV populations supports this hypothesis, recent observations of long-term persistence of individual HCV variants, negative selection increase, and complex dynamics of viral subpopulations during infection as well as broad cross-immunoreactivity (CR) among variants are inconsistent with the immune-escape hypothesis. Here, we present a mathematical model of intrahost viral population dynamics under the condition of a complex CR network (CRN) of viral variants and examine the contribution of CR to establishing persistent HCV infection. The model suggests a mechanism of viral adaptation by antigenic cooperation (AC), with immune responses against one variant protecting other variants. AC reduces the capacity of the host's immune system to neutralize certain viral variants. CRN structure determines specific roles for each viral variant in host adaptation, with variants eliciting broad-CR antibodies facilitating persistence of other variants immunoreacting with these antibodies. The proposed mechanism is supported by empirical observations of intrahost HCV evolution. Interference with AC is a potential strategy for interruption and prevention of chronic HCV infection.hepatitis C | viral quasispecies | cross-immunoreactivity | complex network | intrahost adaptation H epatitis C virus (HCV) causes chronic infection in ∼ 70% of infected people, who become at risk for developing severe liver diseases (1). The virus establishes chronic infection by using several molecular mechanisms for averting innate immunity and attenuating effectiveness of adaptive immune responses (2). HCV is one of the most heterogeneous viruses infecting humans and exists in each infected host as a population of genetically related variants (3, 4). Substantial heterogeneity and drastic changes in genetic composition of the intrahost HCV population observed during chronic infections have been interpreted as evidence of a continuous immune escape via random mutations, thereby generating increasing genetic diversity of viral populations in infected individuals (5-7).The observed cross-immunoreactivity (CR) of HCV variants from earlier stages of infection with antibodies (Abs) from later stages and ineffectiveness of Abs to immunoreact with variants from the same stage of infection (7) seemingly support the hypothesis of immune escape as a mechanism of intrahost evolution that contributes to establishment of persistent infections. However, several recent observations are incompatible with this hypothesis. First, the intrahost HIV population diversifies and diverts continuously from acute state to chronic infection until, at the onset of immunodeficiency, it starts losing heterogeneity and eventually stops diverting (8). Surprisingly, a similar temporal pattern of diversity and diversion was observed for intraho...

show abstract

Section: Discussionmentioning

confidence: 99%

“…Immune responses r i are stimulated by jth variants at rates g j,i x j , where g j,i represents the probability of stimulation of immune response r i by variant x j . It is assumed that x j preferentially stimulates preexisting immune responses capable of binding to x j with a relatively high affinity (33), and thus g j,i is calculated as…”

Section: Modelmentioning

confidence: 99%

Antigenic cooperation among intrahost HCV variants organized into a complex network of cross-immunoreactivity

Skums

Bunimovich

Khudyakov

2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Due to antigenic variability and immune evasion of circulating strains, yearly vaccinations (based on current strain in the population) need to be performed. [25][26][27] A universal influenza vaccine has been an important objective for decades and there have been many failed attempts to design such a vaccine.…”

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

View full text Add to dashboard Cite

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.

show abstract

“…Cross-reactivity has been suggested as a mechanism to evade the immune response in a number of human pathogens, including influenza virus (19), Streptococcus pneumoniae (20), and schistosomiasis (21). In this study, we describe a model that combines variant switching with cross-reactive immune responses to determine the most effective and likely manner for producing chronic asymptomatic infections despite a limited var gene repertoire.…”

mentioning

confidence: 99%

Cross-Reactive Immune Responses as Primary Drivers of Malaria Chronicity

et al. 2014

View full text Add to dashboard Cite

The within-host dynamics of an infection with the malaria parasite Plasmodium falciparum are the result of a complex interplay between the host immune system and parasite. Continual variation of the P. falciparum erythrocyte membrane protein (PfEMP1) antigens displayed on the surface of infected red blood cells enables the parasite to evade the immune system and prolong infection. Despite the importance of antigenic variation in generating the dynamics of infection, our understanding of the mechanisms by which antigenic variation generates long-term chronic infections is still limited. We developed a model to examine the role of cross-reactivity in generating infection dynamics that are comparable to those of experimental infections. The hybrid computational model we developed is attuned to the biology of malaria by mixing discrete replication events, which mimics the synchrony of parasite replication and invasion, with continuous interaction with the immune system. Using simulations, we evaluated the dynamics of a single malaria infection over time. We then examined three major mechanisms by which the dynamics of a malaria infection can be structured: cross-reactivity of the immune response to PfEMP1, differences in parasite clearance rates, and heterogeneity in the rate at which antigens switch. The results of our simulations demonstrate that cross-reactive immune responses play a primary role in generating the dynamics observed in experimentally untreated infections and in lengthening the period of infection. Importantly, we also find that it is the primary response to the initially expressed PfEMP1, or small subset thereof, that structures the cascading cross-immune dynamics and allows for elongation of the infection.

show abstract

How Can Vaccines Against Influenza and Other Viral Diseases Be Made More Effective?

Cited by 25 publications

References 17 publications

Antigenic cooperation among intrahost HCV variants organized into a complex network of cross-immunoreactivity

Antigenic cooperation among intrahost HCV variants organized into a complex network of cross-immunoreactivity

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

Cross-Reactive Immune Responses as Primary Drivers of Malaria Chronicity

Contact Info

Product

Resources

About