Manipulating the Selection Forces during Affinity Maturation to Generate Cross-Reactive HIV Antibodies

Wang, Shenshen; Mata-Fink, Jordi; Kriegsman, Barry; Hanson, Melissa C.; Irvine, Darrell J.; Eisen, Herman N.; Burton, Dennis R.; Wittrup, K. Dane; Kardar, Mehran; Chakraborty, Arup K.

doi:10.1016/j.cell.2015.01.027

Cited by 190 publications

(415 citation statements)

References 67 publications

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“…Given the vast space of possible mutations, it is perhaps unsurprising that diverged antibodies with specific properties appear to arise rarely, and under seemingly contrived circumstances. Identifying the antigens that bind precursors of broadly neutralizing antibodies, and incrementally evolving lineages through sequential immunizations with these antigens, is an active area of research [132,133]. A more tactical evolutionary approach might be to infer the mutations that limit adaptation, such as those with high fitness cost, and to focus immunogen design on selecting viable solutions.…”

Section: Vaccines To Direct Evolutionmentioning

confidence: 99%

The evolution within us

Cobey

Wilson

Matsen

2015

Phil. Trans. R. Soc. B

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One contribution of 13 to a theme issue 'The dynamics of antibody repertoires'. The B-cell immune response is a remarkable evolutionary system found in jawed vertebrates. B-cell receptors, the membrane-bound form of antibodies, are capable of evolving high affinity to almost any foreign protein. High germline diversity and rapid evolution upon encounter with antigen explain the general adaptability of B-cell populations, but the dynamics of repertoires are less well understood. These dynamics are scientifically and clinically important. After highlighting the remarkable characteristics of naive and experienced B-cell repertoires, especially biased usage of genes encoding the B-cell receptors, we contrast methods of sequence analysis and their attempts to explain patterns of B-cell evolution. These phylogenetic approaches are currently unlinked to explicit models of B-cell competition, which analyse repertoire evolution at the level of phenotype, the affinities and specificities to particular antigenic sites. The models, in turn, suggest how chance, infection history and other factors contribute to different patterns of immunodominance and protection between people. Challenges in rational vaccine design, specifically vaccines to induce broadly neutralizing antibodies to HIV, underscore critical gaps in our understanding of B cells' evolutionary and ecological dynamics.

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Section: Vaccines To Direct Evolutionmentioning

confidence: 99%

The evolution within us

Cobey

Wilson

Matsen

2015

Phil. Trans. R. Soc. B

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“…This is in keeping with the findings of Cottral and Gailiunas who described the induction of a cross-protective response to FMDV following a sequential FMDV challenge model with three different FMDV serotypes (4). Indeed, in silico modeling of the antibody response to HIV infection also suggests that a sequential vaccination regime is likely to better promote the development of a broadly neutralizing response to the immunizing antigen compared to immunization with the same cocktail of antigens at one time point (9). The animals from all of the study groups were culled at the end of their respective studies, the prescapular lymph nodes were removed, and the presence of FMDVspecific ASCs was tested by an ELISpot assay.…”

Section: Discussionmentioning

confidence: 99%

The B Cell Response to Foot-and-Mouth Disease Virus in Cattle following Sequential Vaccination with Multiple Serotypes

Grant

Carr

Kotecha

et al. 2017

J Virol

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Foot-and-mouth disease virus (FMDV) is a highly contagious viral disease. Antibodies are pivotal in providing protection against FMDV infection. Serological protection against one FMDV serotype does not confer interserotype protection. However, some historical data have shown that interserotype protection can be induced following sequential FMDV challenge with multiple FMDV serotypes. In this study, we have investigated the kinetics of the FMDV-specific antibody-secreting cell (ASC) response following homologous and heterologous inactivated FMDV vaccination regimes. We have demonstrated that the kinetics of the B cell response are similar for all four FMDV serotypes tested following a homologous FMDV vaccination regime. When a heterologous vaccination regime was used with the sequential inoculation of three different inactivated FMDV serotypes (O, A, and Asia1 serotypes) a B cell response to FMDV SAT1 and serotype C was induced. The studies also revealed that the local lymphoid tissue had detectable FMDV-specific ASCs in the absence of circulating FMDV-specific ASCs, indicating the presence of short-lived ASCs, a hallmark of a T-independent 2 (TI-2) antigenic response to inactivated FMDV capsid.IMPORTANCE We have demonstrated the development of intraserotype response following a sequential vaccination regime of four different FMDV serotypes. We have found indication of short-lived ASCs in the local lymphoid tissue, further evidence of a TI-2 response to FMDV. KEYWORDS B cell, FMDV, T-independent, viral immunology F oot-and-mouth disease virus (FMDV) is a highly contagious pathogen that has a large socioeconomic impact upon countries in which the virus is endemic. Studies of cattle and mice have shown that protection from the virus is largely mediated by antibodies (1). One of the main approaches to FMD control is through vaccination with inactivated FMDV antigen in formulation with adjuvants (2). However, the current inactivated FMDV vaccines are unable to induce long duration of immunity in cattle; regular repeated immunizations are required to maintain protective antibody titers (1).It is generally considered that serological protection against one FMDV serotype does not confer interserotype protection and may not, in some cases, confer intraserotype protection, given the antigenic variation seen within some serotypes (1). We have recently shown that intraserotype protection is possible within the FMDV O serotype using a heterologous FMDV challenge model following a single vaccination with inactivated FMDV (3). Indeed, Cottral and Gailiunas were able to demonstrate that after three rounds of challenge with multiple FMDV serotypes, the animals were resistant to further FMDV challenges (4). These animals had clearly developed cross-

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“…The subsequent maturation of the B-cell response towards bnAb formation is however dependent on exposure to viral variants, that in turn develop under the continued selective pressure of the developing Ab response [73]. Both in silico modelling and experiments in mice seem to indicate that for HIV Env, sequential immunization of these viral variants instead of coadministration is needed for induction of bnAb [74]. However, in the final stages of the immunization cascade, a further broadening of the immune response may require an approach in which multiple variant Env trimers are presented on a single particle, to invoke faster selection of the desired bnAb response through the EDiP described above.…”

Section: Edip For Other Variable Vaccine Antigensmentioning

confidence: 99%

EDiP: the Epitope Dilution Phenomenon. Lessons learnt from a malaria vaccine antigen and its applicability to polymorphic antigens

Kusi

Faber

Koopman

et al. 2017

Expert Review of Vaccines

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Introduction: Polymorphism in vaccine antigens poses major challenges to vaccinologists. The Plasmodium falciparum Apical Membrane Antigen 1 (AMA1) poses such a challenge. We found that immunization with a mixture of three variants yielded functional antibody levels to all variants comparable to levels induced by monovalent immunization. The mechanism behind the observed broadening was shown to be an increase in the fraction of cross-reactive antibodies, most likely because strain-specific epitopes are present at lower frequency relative to conserved epitopes. Areas covered: We hereby introduce the Epitope Dilution Phenomenon (EDiP) as a practical strategy for the induction of broad, cross-variant antibody responses against polymorphic antigens and discuss the utility and applicability of this phenomenon for the development of vaccines against polymorphic antigens of pathogens like Influenza, HIV, Dengue and Plasmodium. Expert commentary: EDiP can be used to broaden antibody responses by immunizing with a mixture of at least 3 antigenic variants, where the variants included can differ, yet yield broadened responses. ARTICLE HISTORY

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Manipulating the Selection Forces during Affinity Maturation to Generate Cross-Reactive HIV Antibodies

Cited by 190 publications

References 67 publications

The evolution within us

The evolution within us

The B Cell Response to Foot-and-Mouth Disease Virus in Cattle following Sequential Vaccination with Multiple Serotypes

EDiP: the Epitope Dilution Phenomenon. Lessons learnt from a malaria vaccine antigen and its applicability to polymorphic antigens

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