The Antibody Germline/Maturation Hypothesis, Elicitation of Broadly Neutralizing Antibodies Against HIV-1 and Cord Blood IgM Repertoires

Prabakaran, Ponraj; Chen, Weizao; Dimitrov, Dimiter S.

doi:10.3389/fimmu.2014.00398

Cited by 15 publications

(10 citation statements)

References 48 publications

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“…BnAbs generally have atypical features compared to the normal antibody repertoire including unusually long heavy chain complementary determining region 3 (CDRH3) or short CDRL3s, autoand poly-reactivity, and/or high levels of somatic hypermutation (SHM) (West et al, 2014;Yu and Guan, 2014). Moreover, many germline-reverted bnAbs have little or no affinity for the HIV envelope trimer (Escolano et al, 2016;Prabakaran et al, 2014). Thus, elicitation of bnAbs within the practical framework of a prime-boost vaccination approach is not trivial.…”

Section: Introductionmentioning

confidence: 99%

Mapping polyclonal antibody responses in non-human primates vaccinated with HIV Env trimer subunit vaccines

Nogal

Bianchi

Cottrell

et al. 2019

Preprint

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Rational immunogen design aims to focus antibody responses to vulnerable sites on the primary antigens. Given the size of these antigens there is however potential for eliciting unwanted, off-target responses. Here, we used our electron microscopy polyclonal epitope mapping approach to describe the antibody specificities elicited by immunization of non-human primates with soluble HIV envelope trimers and subsequent repeated viral challenge. An increased diversity of epitopes recognized, and the approach angle by which these antibodies bound, constituted a hallmark of the humoral response in most protected animals. We also show that fusion peptide-specific antibodies are responsible for some neutralization breadth. Moreover, cryoEM analysis of a fully-protected animal revealed a high degree of clonality within a subset of putatively neutralizing antibodies, enabling a detailed molecular description of the antibody paratope. Our results provide important insights into the immune response against a vaccine candidate that entered into clinical trials earlier this year.

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Section: Introductionmentioning

confidence: 99%

Mapping polyclonal antibody responses in non-human primates vaccinated with HIV Env trimer subunit vaccines

Nogal

Bianchi

Cottrell

et al. 2019

Preprint

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show abstract

“…The aim is to drive the human immune response towards highly mutated anti-HIV-1 bnAbs by using sequential immunizations with various Env immunogens. Several teams have successfully analyzed the paths along which anti-HIV-1 bnAbs develop [58][59][60][61][62][63][64][65][66] but it is not clear yet whether unravelling large numbers of different antibody maturation pathways [67] will make it possible to identify a series of effective immunogens suitable for vaccinating large human populations.…”

Section: Discussionmentioning

confidence: 99%

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

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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.

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“…The difficulties in designing an epitope-based vaccine capable of eliciting broadly neutralizing antibody responses is compounded by the extensive affinity maturation process that anti-HIV neutralizing antibodies undergo before acquiring the broadly neutralizing characteristics ( 39 ). This challenge is being addressed by the use of sequential immunization with different HIV envelope immunogens designed to guide the evolution of the antibody, triggering the selection and expansion of germline precursor and intermediate memory B cells to recapitulate B cell ontogenies associated with the maturation of a broadly neutralizing antibody response ( 40 , 41 ), a concept that had been proposed several years before ( 42 ). Others, perhaps more practical approaches, have been proposed to develop a globally relevant HIV vaccine capable of protecting against a variety of strains and clades ( 43 ), including the use of mosaic immunogens ( 29 , 44 ).…”

Section: Current Hiv Vaccine Paradigm and Drifts That Have Occurred Omentioning

confidence: 99%

A New Scientific Paradigm may be Needed to Finally Develop an HIV Vaccine

Esparza

2015

Front. Immunol.

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The bulk of current HIV vaccine research is conducted within the infectious disease paradigm that has been very successful in developing vaccines against many other viral diseases. Different HIV vaccine concepts, based on the induction of neutralizing antibodies and/or cell mediated immunity, have been developed and clinically tested over the last 30 years, resulting in a few small successes and many disappointments. As new scientific knowledge is obtained, HIV vaccine concepts are constantly modified with the hope that the newly introduced tweaks (or paradigm drifts) will provide the solution to one of the most difficult challenges that modern biomedical research is confronting. Efficacy trials have been critical in guiding HIV vaccine development. However, from the five phase III efficacy trials conducted to date, only one (RV144) resulted in modest efficacy. The results from RV144 were surprising in many ways, including the identified putative correlates of protection (or risk), which did not include neutralizing antibodies or cytotoxic T-cells. The solution to the HIV vaccine challenge may very well come from approaches based on the current paradigm. However, at the same time, out-of-the-paradigm ideas should be systematically explored to complement the current efforts. New mechanisms are needed to identify and support the innovative research that will hopefully accelerate the development of an urgently needed HIV vaccine.

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The Antibody Germline/Maturation Hypothesis, Elicitation of Broadly Neutralizing Antibodies Against HIV-1 and Cord Blood IgM Repertoires

Cited by 15 publications

References 48 publications

Mapping polyclonal antibody responses in non-human primates vaccinated with HIV Env trimer subunit vaccines

Mapping polyclonal antibody responses in non-human primates vaccinated with HIV Env trimer subunit vaccines

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?

A New Scientific Paradigm may be Needed to Finally Develop an HIV Vaccine

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