An Outdated Notion of Antibody Specificity Is One of the Major Detrimental Assumptions of the Structure-Based Reverse Vaccinology Paradigm, Which Prevented It from Helping to Develop an Effective HIV-1 Vaccine

Regenmortel, M.H.V. Van

doi:10.1007/978-3-030-32459-9_17

Cited by 2 publications

(4 citation statements)

References 100 publications

(108 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The structure-based rational design of an HIV-1 vaccine is based on the assumption that knowledge of the structure of vulnerable Env epitopes targeted by bnMabs will lead to the discovery of effective HIV-1 vaccine immunogens [4,14,41,42]. After many years of unsuccessful experimentation by numerous laboratories, Mascola and Haynes in 2013 concluded that "our best attempts to construct vaccine immunogens that present these key epitopes to the immune system have failed to generate antibodies that neutralize most strains of HIV-1" and they acknowledged that "a structure-based approach in and of itself will likely not solve the HIV-1 vaccine problem" [13].…”

Section: Discussionmentioning

confidence: 99%

“…Another limitation inherent in the use of Mabs for helping to develop an HIV-1 vaccine arises from the polyspecificity of antibody molecules [4,8,43]. In view of the degenerate nature of the immune system, there is no single intrinsically specific epitope for any Ab but only a diverse group of potential epitopes able to bind to it with various degrees of fit [44][45][46][47].…”

Section: Dissecting the Antigenic Structure Of Hiv-1 With Mabs Has Unmentioning

confidence: 99%

“…It has been suggested that our inability over the past 25 years to develop an effective HIV vaccine is partly due to the fact that investigators adhered to several unwarranted assumptions and paradigms that made them pursue unfruitful research strategies [1,2]. One such misleading assumption central to the structure-based reverse vaccinology approach [3] was the belief that when an HIV-1 Env epitope is found to bind to a broadly neutralizing monoclonal antibody (bnMab), this epitope should also be able to induce similar neutralizing antibodies when used as an immunogen [4]. A related assumption was that HIV-1 Env epitopes, targeted by hypermutated bnMabs that are produced in HIV-1 infected individuals after a lengthy process of antibody affinity maturation, would be able to trigger a protective immune response in naive individuals [5,6].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Why Does the Molecular Structure of Broadly Neutralizing Monoclonal Antibodies Isolated from Individuals Infected with HIV-1 Not Inform the Rational Design of an HIV-1 Vaccine?

Regenmortel¹

2019

HIV/AIDS: Immunochemistry, Reductionism and Vaccine Design

Self Cite

View full text Add to dashboard Cite

It is commonly assumed that neutralizing Mabs that bind to the HIV-1 Env glycoprotein are more specific reagents than anti-HIV-1 polyclonal antisera and that knowledge of the structure of these Mabs facilitates the rational design of effective HIV-1 vaccine immunogens. However, after more than ten years of unsuccessful experimentation using the structure-based reverse vaccinology approach, it is now evident that it is not possible to infer from the structure of neutralizing Mabs which HIV immunogens induced their formation nor which vaccine immunogens will elicit similar Abs in an immunized host. The use of Mabs for developing an HIV-1 vaccine was counterproductive because it overlooked the fact that the apparent specificity of a Mab very much depends on the selection procedure used to obtain it and also did not take into account that an antibody is never monospecific for a single epitope but is always polyspecific for many epitopes. When the rationale of the proponents of the unsuccessful rational design strategy is analyzed, it appears that investigators who claim they are designing a vaccine immunogen are only improving the binding reactivity of a single epitope-paratope pair and are not actually designing an immunogen able to generate protective antibodies. The task of a designer consists in imagining what type of immunogen is likely to elicit a protective immune response but in the absence of knowledge regarding which features of the immune system are responsible for producing a functional neutralizing activity in antibodies, it is not feasible to intentionally optimize a potential immunogen candidate in order to obtain the desired outcome. The only available option is actually to test possible solutions by trial-and-error experiments until the preset goal is perhaps attained. Rational design and empirical approaches in HIV vaccine research should thus not be opposed as alternative options since empirical testing is an integral part of a so-called design strategy.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Dissecting the Antigenic Structure Of Hiv-1 With Mabs Has Unmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Why Does the Molecular Structure of Broadly Neutralizing Monoclonal Antibodies Isolated from Individuals Infected with HIV-1 Not Inform the Rational Design of an HIV-1 Vaccine?

Regenmortel¹

2019

HIV/AIDS: Immunochemistry, Reductionism and Vaccine Design

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is also remarkable that the unsuccessful SBRV approach was pursued for more than 15 years, although its underlying paradigm was shown to be incompatible with well‐established immunological theory such as the degeneracy of the immune system and the polyspecificity and heterospecificity of antibodies . However, these shortcomings have never been recognized or addressed by the proponents of SBRV .…”

Section: Paradigms and The Rational Design Of An Hiv Vaccinementioning

confidence: 99%

Truth in science and in molecular recognition, post‐truth in human affairs

Regenmortel

2019

J of Molecular Recognition

View full text Add to dashboard Cite

An Outdated Notion of Antibody Specificity Is One of the Major Detrimental Assumptions of the Structure-Based Reverse Vaccinology Paradigm, Which Prevented It from Helping to Develop an Effective HIV-1 Vaccine

Cited by 2 publications

References 100 publications

Why Does the Molecular Structure of Broadly Neutralizing Monoclonal Antibodies Isolated from Individuals Infected with HIV-1 Not Inform the Rational Design of an HIV-1 Vaccine?

Why Does the Molecular Structure of Broadly Neutralizing Monoclonal Antibodies Isolated from Individuals Infected with HIV-1 Not Inform the Rational Design of an HIV-1 Vaccine?

Truth in science and in molecular recognition, post‐truth in human affairs

Contact Info

Product

Resources

About