Editorial: Paradigm Changes are Required in HIV Vaccine Research

摘要

In his influential book “The Structure of Scientific Revolutions” published in 1962, Thomas Kuhn argued that researchers in every field of scientific enquiry are always guided by theoretical assumptions, presuppositions, and hypotheses that constitute the prevailing scientific paradigm under which they operate at any given time ( 1 ). When they operate within a shared paradigm, a scientific community working in a particular field will be committed to using certain strategies and experimental approaches that are accepted as being essential for trying to solve the problem at hand.In many cases, the implicit hypotheses and presuppositions that give rise to a particular paradigm are not clearly stated and investigators may therefore sometimes not even be aware of them. One consequence of this is that when they obtain results that are not compatible with the theory and hypotheses underlying the paradigm, they may fail to appreciate that their guiding paradigm has in fact been refuted and should therefore be abandoned or revised. On the other hand, according to Kuhn, scientists actually do not abandon their hypotheses and paradigms as soon as contradictory data are obtained, since their main goal is not to try to confirm the validity of the underlying assumptions of their paradigms. Scientific communities tend to remain committed to their shared theoretical beliefs even when they obtain anomalous results that are not consistent with the paradigm, and they will invent new ad hoc hypotheses in an attempt to resolve apparent contradictions between theory and experimental observations ( 2 ). Unfortunately, when misleading paradigms are not discarded, this may encourage scientists to pursue unfruitful lines of investigations that could impede scientific progress.In the field of HIV vaccine research, there is in fact evidence that in recent years a number of paradigms based on invalid assumptions had such a detrimental effect ( 3 ). This drawback can only be avoided if scientists keep in mind that if the paradigms they have adopted are based on erroneous assumptions, this could lead them to select inappropriate research strategies that are unlikely to succeed. Questioning the validity of paradigms is thus an important safeguard since it may reveal which invalid assumptions have led investigators astray in the past. Only when past mistakes are acknowledged can novel paradigms be introduced, which better fit our improved knowledge of HIV-1 immune responses, and are therefore more likely to help future vaccine development ( 4 , 5 ).The following unwarranted assumptions underlying some popular paradigms in HIV vaccine research may have contributed to our inability during the past 25?years to develop an effective HIV-1 vaccine. Assumption No. 1: Vaccine Immunogenicity can be Predicted from Viral Antigenicity Most fragments of a viral antigen are immunogenic and are able to induce antibodies that will react with the fragment. However, this type of immunogenicity is irrelevant for vaccination since these antibodies rarely recognize the cognate, intact antigen, and even more rarely neutralize the infectivity of the viral pathogen that harbors the antigen ( 6 ). A confusion between biological immunogenicity (the ability to induce antibodies in a host) and chemical antigenicity (the capacity of an antigen to bind antibodies) lies at the heart of the reverse vaccinology paradigm that has been pursued vigorously for more than 10?years. According to this paradigm, HIV-1 epitopes identified by X-ray crystallographic analysis of complexes of HIV Env bound to affinity-matured neutralizing monoclonal antibodies (nMabs) were expected to be also effective vaccine immunogens able to induce a protective immune response. However, an epitope that binds to a nMab will not necessarily be able to induce the same type of neutralizing antibody in an immunized host. As discussed at length elsewhere ( 7 ), investigators who claim they are designing a vaccine immunogen are only improving the binding reactivity (i.e., the antigenicity) of a single epitope–paratope pair and are not actually designing a vaccine immunogen able to generate protective antibodies. Immunogenicity does depend on numerous factors that exist only in the context of the host immune system, and these are independent of the binding properties of the viral antigen used for immunization ( 8 ). Assumption No. 2: There is a Primary and Intrinsic Epitope Specific for Each B Cell Receptor and its Corresponding Antibody In reality, there is no single intrinsic epitope for any antibody molecule but only a diverse group of potential ligands able to bind to it with various degrees of fit ( 3 ). Vaccinologists have been slow to accept that antibodies are not monospecific for a single epitope and that the degeneracy of the immune system always makes antibodies polyspecific for numerous related or unrelated epitopes present in different antigens ( 9 – 11 ). Once it is accepted that the epitop