An Outdated Notion of Antibody Specificity is One of the Major Detrimental Assumptions of the Structure-Based Reverse Vaccinology Paradigm, Which Prevented It from Helping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

Abstract

The importance of paradigms for guiding scientific research is explained with reference to the seminal work of Karl Popper and Thomas Kuhn. A prevalent paradigm, followed for more than a decade in HIV-1 vaccine research, which gave rise to the strategy known as structure-based reverse vaccinology is described in detail. Several reasons why this paradigm did not allow the development of an effective HIV-1 vaccine are analyzed. A major reason is the belief shared by many vaccinologists that antibodies possess a narrow specificity for a single epitope and are not polyspecific for a diverse group of potential epitopes. When this belief is abandoned, it becomes obvious that the one particular epitope structure observed during the crystallographic analysis of a neutralizing antibody–antigen complex does not necessarily reveal, which immunogenic structure should be used to elicit the same type of neutralizing antibody. In the physical sciences, scientific explanations are usually presented as logical deductions derived from a relevant law of nature together with certain initial conditions. In immunology, causal explanations in terms of a single cause acting according to a law of nature are not possible because numerous factors always play a role in bringing about an effect. The implications of this state of affairs for the rational design of HIV vaccines are outlined. An alternative approach to obtain useful scientific understanding consists in intervening empirically in the immune system and it is suggested that manipulating the system experimentally is needed to learn to control it and achieve protective immunity by vaccination.

Immune Epitope Continuum of the Protein Relationships, Poly- And Autoreactivity of Antibodies

“…Кажущаяся с первого взгляда привлекательной идея создания клеточ-ных вакцин, специфичных к строго определен-ному набору ИЭ, чревата опасностью из-за воз-можности индукции ими аутоиммунной реакции у реципиента. В русле «здравого смысла» кажутся и попытки ретровакцинологии преодолеть не-удачи с поисками вакцин против ВИЧ и вируса гриппа через индукцию иммунитета подобран-ными консервативными ИЭ белков этих вирусов, основанного на образовании Ат с высокой авид-ностыо и широким спектром действия и ней-трализующих многие штаммы соответствующих вирусов [36]. Но нейтрализующие Ат с широким спектром действия специфичны к консерватив-ным фрагментам белков вирусов, которые часто оказываются гомологичными фрагментам бел-ков хозяина и характеризуются недостаточной иммуногенностью [16,21].…”

“…Независимо от их источника общим свой-ством Ig являются полиреактивность и аутореак-тивность, особенно в случае ЕА [31]. Еще 30 лет назад было признано, что и моноклональные Ат всегда полиспецифичные [36]. Соответственно, возникает вопрос: обусловлена ли полиауторе-активность Ат только их конформационной мо-бильностью или она определяется также свой-ствами самих белков, с которыми они наиболее часто взаимодействуют.…”

The Impact of Bioinformatics on Vaccine Design and Development

“…If a vaccine that induces a cellular response is needed, for example a tuberculosis vaccine [22] or a parasite vaccine against leishmaniasis [23], the software must search for antigens that can be recognized by the major histocompatibility complex (MHC) molecules present in T lymphocytes [4]. On the other hand, if a humoral response is required, the software needs to identify antigens for B cells, for example, in the case of inluenza virus or HIV [24,25]. There is software that speciically searches for sequential epitopes for B cells, including BCPREDS, BepiPred, BEpro or PEPITO, ABCpred, Bcepred, IgPred, and BCEP.…”

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

“…[54][55][56][57][58][59] We share the opinion that reverse vaccinology, based on the combined use of genomic, structural and immunological information to select relevant protective HIV-1 epitopes with increased antigenicity, may not lead to the discovery of effective immunogens: in other words, vaccine immunogenicity can not be predicted from viral antigenicity. 60,61 Clearly, alternative innovative paradigms that could diversify the further search for vaccine candidates are needed. 59,60 Recently, an important role of viral antigenic diversity in shaping of bnAb repertoires was analyzed in detailed and systematic manner.…”

“…60,61 Clearly, alternative innovative paradigms that could diversify the further search for vaccine candidates are needed. 59,60 Recently, an important role of viral antigenic diversity in shaping of bnAb repertoires was analyzed in detailed and systematic manner. 61 Thus, the effect of diverse HIV variant epitopes (immunotypes) on driving the neutralization breadth within a family of 33 mAbs, isolated from a superinfected patient was studied demonstrating that early viral escape at key antibodyvirus contact sites selects for antibodies that can tolerate these changes.…”