Design in biology and rational design in vaccinology: A conceptual analysis

Regenmortel, M.H.V. Van

doi:10.1016/j.ymeth.2021.07.010

Cited by 3 publications

(1 citation statement)

References 39 publications

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“…All these observations and considerations bring serious doubts about the overall applicability of the rational structural vaccinology computational methods. These concerns are further elaborated and enhanced by an important fact that when the proteins interact, they often undergo mutual adaptation and induced fit/folding [36,[110][111][112], indicating that epitopes and paratopes are fuzzy binding sites devoid of clear-cut structural boundaries [113]. As a result, the structures of the binding sites in the unbound molecules may dramatically differ from the static structures of antigen-Ab complexes used in the rational structural vaccinology [113][114][115][116].…”

Section: Concluding Remarks: Fight Fire With Firementioning

confidence: 99%

Fight fire with fire: the need for a vaccine based on intrinsic disorder and structural flexibility

Uversky

2022

Explor Immunol

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The absence of advancement in finding efficient vaccines for several human viruses, such as hepatitis C virus (HCV), human immunodeficiency virus type 1 (HIV-1), and herpes simplex viruses (HSVs) despite 30, 40, and even 60 years of research, respectively, is unnerving. Among objective reasons for such failure are the highly glycosylated nature of proteins used as primary vaccine targets against these viruses and the presence of neotopes and cryptotopes, as well as high mutation rates of the RNA viruses HCV and HIV-1 and the capability to establish latency by HSVs. However, the lack of success in utilization of the structure-based reverse vaccinology for these viruses is likely to be related to the presence of highly flexible and intrinsically disordered regions in human antibodies (Abs) and the major immunogens of HIV-1, HCV, and HSVs, their surface glycoproteins. This clearly calls for moving from the rational structure-based vaccinology to the unstructural vaccinology based on the utilization of tools designed for the analysis of disordered and flexible proteins, while looking at intrinsically disordered viral antigens and their interactions with intrinsically disordered/flexible Abs.

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Section: Concluding Remarks: Fight Fire With Firementioning

confidence: 99%

Fight fire with fire: the need for a vaccine based on intrinsic disorder and structural flexibility

Uversky

2022

Explor Immunol

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Toward interdisciplinary methods appropriate for optimal epidemic control

Rivas

Regenmortel

2021

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Paradigms in HIV vaccine research

Regenmortel

2022

Explor Immunol

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Although a large number of preventative human immunodeficiency virus (HIV) vaccine trials have been carried out during the last 30 years, it is remarkable that an effective HIV vaccine has not yet been developed. Research paradigms correspond to theoretical assumptions and particular strategies that scientists use when they try to solve a particular problem. Many paradigms used successfully in vaccinology were ineffective with HIV. For instance: 1) The structure-based reverse vaccinology approach failed because investigators tried to generate a vaccine starting with the antigenic structure of HIV-envelope (Env) epitopes bound to neutralizing monoclonal antibodies (mAbs) derived from HIV-infected individuals. They assumed that this antigenic structure would also possess the immunogenic capacity of inducing in vaccinees a polyclonal antibody (Ab) response with the same neutralizing capacity as the mAb. 2) The structures observed in epitope-paratope crystallographic complexes result from mutually induced fit between the two partners and do not correspond to the structures present in the free molecules before they had interacted. 3) The affinity-matured neutralizing mAbs obtained from chronically infected individuals did not recognize the germline predecessors of these Abs present in vaccinees. 4) The HIV p17 matrix protein that lines the inner surface of the viral membrane is one of the most disordered proteins identified on our planet and this prevents the induced Abs from binding to the glycosylated HIV gp120 protein. 5) Vaccinologists need to solve so-called inverse problems, for instance, guessing what are the multiple causes that produced an earlier wanted beneficial effect such as the absence of deleterious HIV infection in elite controllers. Since the immune system consists of numerous subsystems that have not yet been elucidated, it is impossible to solve the inverse problems posed by each subsystem. 6) Vaccinology is an empirical science that only sometimes succeeds because we do not understand the complex mechanisms that lead to protective immune responses.

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Design in biology and rational design in vaccinology: A conceptual analysis

Cited by 3 publications

References 39 publications

Fight fire with fire: the need for a vaccine based on intrinsic disorder and structural flexibility

Fight fire with fire: the need for a vaccine based on intrinsic disorder and structural flexibility

Toward interdisciplinary methods appropriate for optimal epidemic control

Paradigms in HIV vaccine research

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