in an effort to develop effective vaccines against pathogens that severely affect humans , the concept of original antigenic sin ( oas ) has become a guiding light , making sense of baffling observations on the infection profiles of foreign pathogens and vaccine efficacies in humans .
oas was first described by davenport et al . to explain antibody responses that were generated after influenza virus infection in people of different age groups ( 1 ) .
it was then suggested that antibody - forming mechanisms appear to be directed by initial childhood infections , such that exposure to antigenically related strains later in life results in progressive reinforcement of the primary antibody . according to this suggestion
, oas might ' freeze ' the immune repertoire against a pathogen ( 2 ) .
the repertoire freeze mechanism of oas is understood as part of the hard - coded immune memory responses against a potential recurring pathogen ( 3 ) .
recent research has shown that though it appears to be pathogen - dependent , such a memory response is also found during innate immune responses , and is not limited to adaptive immunity ( 4 ) .
this mechanism would protect the host from the pathogen like a well - trained defense team .
immunity against measles , mumps , and smallpox , among others , is a good example of memory responses that provide lifetime protection after a single natural infection or an effective vaccination ( 45 ) .
unfortunately , most pathogens adapt to this immune program by constantly changing their surface molecules .
the reason why oas is stigmatized as ' sin ' is its interference with the nave immune response against variants of the pathogen ( 6 ) . in this review ,
we introduce the concept of oas as a type of ' immune repertoire freezing ' , the result of which can have both positive and negative impacts on immune responses against pathogens and on the course of diseases caused by such agents .
the epitome of memory responses in the immune system is the rapid production of antibodies of different isotypes and effector cytokines such as ifn - g or interleukins , by antigen specific b lymphocytes ( b cells ) and the cognate thymus - derived lymphocytes ( t cells ) , respectively ( 7 ) .
phenotypically defined memory b and t cells have been shown to divide more rapidly than naive cells ( 789 ) .
oas , a process of repertoire freeze in memory responses ( 3101112 ) are shown in fig .
1 . when an antigen specific receptor ( bcr ) on the outer surface of b cells recognizes its cognate antigen of a pathogen , the b cell captures and processes the pathogen by presenting pieces of the antigen onto major histocompatibility complex class ii ( mhc ii ) molecules .
a single b cell recognizes a single antigen on a pathogen , but can present as many as antigens of the pathogen on mhc ii molecules for recognition of cd4 + t cells via a cognate t cell receptors ( tcrs ) . through this interaction , both antigen - specific b and t cells can proliferate and differentiate into plasma or memory b cells and effector or memory t cells , respectively , depending on environments of the interaction ( 131415 ) . when an antigenic variant of the same pathogen appears , it is likely to be captured by memory b cells , which can recognize a conserved or cross - reactive recognition site ( epitope ) of the pathogen rather than by a nave b cells .
this is because memory b cells are expanded clones against the same specific antigen from the previous exposures to the antigen , whereas nave b cells originate from unique vdj recombinations , resulting in a repertoire that might not efficiently respond to a specific epitope . before affinity maturation through a somatic hypermutation process , in part mediated by t cells , the affinity of the target to the bcr on the nave b cells is generally low ( 16 ) .
therefore , even though antigen - specific nave b cells recognize a dominant antigenic site , they might not have an advantage in terms of competition for antigen capture over cross - reactive memory b cells .
furthermore , memory immune responses might help to rapidly clear the pathogen through limiting the availability of the antigen for variant specific nave b cells ( 1718 ) .
serum antibody , fc receptor ( fcr)-mediated non - specific capture , or presentation of the mhc ii antigens by antigen presenting cells ( apcs ) bearing other fcr , such as macrophages and dendritic cells ( dcs ) ( 19 ) , are also likely to further enrich antigen - specific memory t cells from a previous exposure , rather than antigen - specific nave t cell activation , this occurs for the previously stated reason , specifically , that of better availability of memory t cells than antigen - specific nave t cells . as shown in fig .
1 , it is conceivable that a dominant antigenic site - specific nave b cells happen to encounter the cognate epitope before the clearance of the pathogen by the cross - reactive memory b cell responses . this would be followed by activation of cognate memory t cells from previous exposures .
although the dominant response is repertoire freeze , antibody diversification may occur against different influenza strains through time ( 1 ) , which can suggest that the frozen repertoire can melt and be imbued with some diversity . with regard to the memory immune response , increased diversity is an important concept for vaccine design .
while oas is harnessed by many universal influenza vaccine strategies ( 2021222324 ) , oas - mediated generation of cross - reactive , non - neutralizing antibodies against pathogens such as dengue virus can be a cause of enhanced disease severity after the second infection , which represents a hurdle for vaccine development ( 22526 ) .
the conceptual aim of a universal vaccine is to achieve optimal memory b cell and/or t cell responses toward a conserved epitope of a recurring and constantly changing pathogen , through a single immunization .
however , it appears natural for the pathogen to change its surface antigenic region for survival , because the region typically harbors an immunodominant epitope , which poses a dilemma for universal vaccine strategies . in table
i , we summarize , albeit not extensively , the aspects of viral vaccine design as they relate to mechanisms of oas , assuming recurring infections by the same pathogen with antigenic variation . overcoming oas is an important issue in terms of a vaccine development against recurring pathogens such as seasonal influenza viruses , because a vaccine strategy stimulating repertoire diversification would change the efficacy of the vaccine upon the appearance of variant strains .
conceivably , a repertoire freeze can be somewhat overcome by removing the limitation of antigen availability , even though there can be practical limitations to this .
the use of more antigens for an inactivated influenza vaccine was shown to be associated with higher influenza - specific antibody titers in the serum of vaccinated hiv patients , compared to that observed with a lower number of antigens ( 27 ) . a cohort study of healthy adults vaccinated with a virus - like , virosomal , trivalent inactivated influenza vaccine ( tiv ; including antigens from h1n1 , h3n2 , and influenza b viruses ) or with a split tiv showed higher influenza - specific igm responses with the split vaccine cohort compared to that with the virosomal vaccine cohort ( 28 ) . in the same study , hiv patients in the virosomal vaccine cohort showed qualitatively similar immune responses as healthy subjects , and a difference was only quantitatively identified .
igm is the first antibody isotype secreted by short - lived plasma cells , and is generated in the initial proliferation and expansion phase in antigen - specific naive b cells , before a t cell - mediated isotype class switch occurs ( 29 ) . because of this , igm responses might be considered representative of nave immune responses .
similarly , there have been reports demonstrating that a live - attenuated influenza vaccine ( laiv ) is more effective in children , whereas the split tiv is more effective in adults ( 303132 ) .
it is likely that the split tiv could allow the immune system of adults , harboring the accumulated effects of oas , to expand its diversity , compared to that with laiv .
split tiv can minimize the oas - dominated ' winner takes all ' situation in the competition for antigen capturing ( fig .
2 ) . in the case of split / subunit vaccines for adults , some subdominant but conserved epitopes can be exposed to nave or memory b cells that can be activated by cognate memory t cells .
although no dna vaccine has been licensed against influenza , it could potentially work like split / subunit and live vaccines .
if such dna is for non - specific expression and for the release of encoded viral proteins , its vaccine effects will theoretically be similar to those of split / subunit vaccines .
for dna delivery , targeting to apcs , memory b cells , and t cells can be achieved , which could result in the laiv - like effects without the aforementioned ' winner take all ' competition for antigens , which might eventually support repertoire diversification .
it appears that the vaccine preparation method can determine the magnitude of nave immune responses , or in other words , repertoire diversification , as shown in table i. such repertoire diversification efforts might give a chance to the dominant epitopes of a predicted variant , which could undergo further variation .
however , in the context of immune memory generated by such strategies against conserved subdominant epitopes , whether corresponding conserved epitope - specific memory b cells will be able to gain access to the antigen beyond dominant epitope cross - reactive memory b cells in the event of a new variant infection ( 3334 ) , is another issue ( fig .
regardless of the methods of vaccination , upon exposure to an unpredicted variant pathogen , clearance may occur through a ' good ' oas or , a ' good ' oas and/or the development of a diversified immune repertoire from nave immune responses against the variant epitopes by prolonged exposure to the pathogen .
this implies that the pathogen could have enough time to grow and harm the host before being cleared .
the evidence for ' good ' ( or beneficial ) oas is difficult to discern . in the cases of influenza vaccination ,
a mismatched vaccine is not ' optimally ' protective , although the mismatch often stems from a difference of only a few amino acids in the globular heads of the hemagglutinin between the vaccine strain and the circulating strain ( 353637 ) .
however , as observed during the 2009 h1n1 influenza pandemic , even if mismatched , vaccination with a tiv ( including seasonal h1n1 virus components ) in the previous season proved to be beneficial , as unvaccinated individuals suffered more severe disease outcomes ( 31 ) .
this suggests that marginal but beneficial cross - reactivity from oas can help to fight against the influenza virus .
the 2009 h1n1 influenza pandemic helped us gain a better understanding of immune responses against influenza virus infection . when donor sera taken before and after seasonal influenza vaccination ( 2007 - 08 or 2008 - 09 season ) were analyzed for cross - reactivity to the pandemic 2009 h1n1 influenza virus ( p2009 h1n1 ) , adults older than 60 were shown to have a high rate of preexisting immunity ( 38 ) .
interestingly , the sera of older adults taken before seasonal vaccination showed a higher microneutralization antibody titer against p2009 h1n1 than against the seasonal h1n1 ; in addition , the titer against p2009 h1n1 increased slightly after seasonal vaccination , which was understandably not to the level of antibody titer increase against seasonal h1n1 .
individuals born closer to 1918 showed a higher protective microneutralization titer against p2009 h1n1 ( 38 ) , suggesting that specific humoral immunity against the influenza virus can be very long lasting .
it is very likely that immune memory to the conserved epitope(s ) of the 1918 and p2009 h1n1 strains has been continuously boosted through years of infections with variant h1n1 strains through the mechanism of oas .
although impossible to confirm , and as suggested by the need for seasonal vaccinations , it is very likely that the continually boosted 1918 h1n1 oas memory is beneficial but not sufficient to defend against continuously changing seasonal variants .
such immune memory was fully protective ( assuming that microneutralization is indicative of protection against the virus in vivo ) only when similar viruses were presented .
so far , we have discussed cases suggesting the beneficial effects of oas against influenza viruses . however , it is apparent that continuous boosting of conserved epitopes through recurrent infections by variant viruses , does not offer complete protection against a new variant infection ; although it sounds like a circular argument , because of lack of protection , infections recur
. otherwise , seasonal vaccination against new variants of the influenza virus would be unnecessary ( 39 ) .
the challenge of a universal vaccine design appears to be the optimization of the ' good ' oas .
a memory b cell repertoire specific for difficult - to - access subdominant conserved epitopes of influenza virus can not be adequately generated in the first place , or not recalled efficiently , or potentially have negative effects on the nave immune responses against a particular variant .
we discussed previously that the generation of a memory b cell repertoire against conserved but difficult - to - access epitopes could be conceptually achieved through a suitable vaccine preparation method .
3 ) ; the potential for this repertoire to contribute to adverse outcomes during influenza virus infection has not been adequately studied .
. however , animal models can not appropriately and exhaustively model the history of vaccination and infection in humans .
comparison of the two h1n1 influenza pandemics of 1918 and 2009 appears to be educational . in terms of diseases
severity , the two pandemics are incomparable ; while some 50 million deaths were estimated in the 1918 pandemic , the estimated number of influenza - related deaths during the 2009 pandemic was no higher than yearly seasonal influenza - related deaths ( 40 ) . in the case of the 2009 pandemic , although in vitro assays showed marginal cross - reactivity between the sera of seasonal tiv - vaccinated healthy adults and p2009 h1n1 , seasonal vaccination was associated with less severe disease outcomes ( 31 ) .
this suggests that some protection was afforded either by the non - neutralizing antibodies against the conserved epitopes potentially through the fcr - mediated protective responses ( 41 ) , or by the memory t cell responses against the conserved epitopes , or by both . in the case of 1918
, records revealed that more young adults ( presumably with robust health ) succumbed to the virus than the children and the elderly individuals ( 42 ) , suggesting that oas might have resulted in adverse effects in immunocompetent adults and that potentially beneficial immune memory in the elderly was protective .
interestingly , in young adults , p2009 h1n1 resulted in a 2~4-fold greater risk of severe outcomes , specifically those requiring intensive care and mechanical ventilation , compared to seasonal influenza ( 43 ) .
this suggests that the 1918 pandemic was actually recapitulated on a small scale during the 2009 pandemic . obviously , the 1918 pandemic was not the first human encounter with the influenza virus ( 44 ) .
we can assume that individuals must have had some level of immunity against the influenza virus through recurring natural infections , which could be considered a form of whole virus vaccination .
from such type of vaccination , we can conceptually assume ( fig . 1 and table i ) that people in 1918 had very little b cell memory against conserved but subdominant epitopes of the influenza virus , but undoubtedly had some cd4 and cd8 t cell memory against conserved epitopes of the virus .
if oas had mediated an adverse immune response , involved in the severity of the disease caused by the 1918 h1n1 virus infection , apart from the high virulence of the virus ( 45 ) , the key contributing factors must have been cross - reactive non - neutralizing memory b cell responses against a dominant epitope or memory t cell responses against conserved epitopes .
an important question is whether memory cd4 and cd8 cells that recognize conserved epitopes cause harmful effects in response to an infective viral variant .
protection against the influenza virus through cd4 and cd8 t cell immunity alone was demonstrated in mice ( 4647 ) .
however , although memory cd4 and cd8 cells persist for a long time through homeostatic proliferation ( 1048 ) , cross - protective resident memory cd8 t cells in pulmonary tissues , which are specific for the influenza virus , were shown to be short - lived ( 495051 ) .
these observations from experiments using mice have limitations ; however , they appear to partly explain why infections recur , regardless of conserved epitopes of internal influenza proteins that can potentially generate universally protective memory cd8 t cells .
memory cd4 t cells against conserved epitopes can conceptually function as a " double - edged sword " when faced with a variant ; the cross - reactive oas responses of memory b cells against dominant epitopes , with the help of memory cd4 t cells recognizing conserved epitopes , can be beneficial or damaging ( i.e. ' good ' oas or ' bad ' oas ) . whether a non - neutralizing cross - reactive oas response , with the help of memory cd4 t cells against conserved epitopes , contributed to such devastating manifestations of the1918 h1n1 pandemic h1n1 ( 5253 ) is a matter of speculation .
however , the well - documented effect of ' bad ' oas in dengue virus infection could provide some clues for this issue .
infection with a dengue virus can be asymptomatic or result in dengue fever ( df ) or dengue hemorrhagic fever ( dhf ) .
substantial evidence has associated dhf with secondary infection of a serotype of the dengue virus different from the virus to which an individual has already been exposed .
the most widely accepted hypothesis for the pathogenesis of dhf is antibody - dependent enhancement ( ade ) of dengue virus infection ( reviewed in ( 25 ) ) .
ade depends on pathogen binding antibodies and antibody binding complement proteins and their receptors such as fcrs and complement receptors .
therefore ade is observed mainly with pathogens that efficiently infect fcr - bearing myeloid lineage cells , such as dendritic cells and macrophages ( 2 ) .
dc - sign is a universal receptor for the dengue virus , and dc - sign - expressing immature dcs were shown to be the initial site of infection ( 54 ) .
dengue virus can also infect other fcr - bearing cells of the immune system , such as mature dcs and macrophages .
dengue virus - infected human endothelial cells are capable of antibody - dependent complement activation and undergo apoptosis ( 55 ) .
although conceptually feasible , it is not clear whether the dengue virus - antibody - complement - complement receptor complex on the cell surface can actually enhance infection of dengue virus in endothelial cells .
however , a similar ade mechanism has been observed during infections with other viruses like hiv ( 2 ) .
it has been shown that human endothelial cells are highly susceptible to dengue virus infection ( 56 ) .
uninfected endothelial cells might also participate in the disease process via complement receptors on endothelial cells and platelets that can mediate inflammatory responses ( 5758 ) ; however , the infected endothelium , in the presence of cross - reactive antibodies , might resemble the endothelium of a host experiencing graft rejection ( 59 ) .
ade by itself is not thought to correlate with disease severity and dhf ; complement activation by virus - antibody or antigen - antibody complexes is a feature of severe dengue infection , and it is temporally related to plasma leakage ( 6 ) .
immune responses against dengue viruses are not very different from immune responses against other viruses such as influenza virus .
there are conserved features and differences among the variants , and accordingly , inevitable oas can occur .
an individual infected with one type of dengue virus never succumbs to the same type of dengue virus infection because of its long - lasting homotypic protective immunity against the primary strain ( 6 ) .
however , when the same individual is infected with different serotype of dengue virus , serotype cross - reactive memory b and t cells from the prior exposure become activated
. however , these cross - reactive responses are not protective , and are even detrimental .
it was shown that highly cross - reactive monoclonal antibodies against dengue viruses could be potently neutralizing at an optimal concentration but resulted in ade at a suboptimal concentration ( 60 ) .
it appears that cross - reactive antibodies are not necessarily inherently defective in their neutralization capacity ; however , cross - reactive antibodies incapable of virus neutralization are harnessed by the dengue viruses for ade .
if this outcome is dependent on an optimal ratio of antibody to pathogen , ade is theoretically possible for any pathogen that can productively infect fcr- and complement receptor - bearing cells ( 2 ) .
non - neutralizing antibodies against the influenza virus were shown to be protective ( 41 ) , most likely through fcr and complement - mediated pathways .
however , in the case of dengue virus infection , cells that are involved in such protective pathways augment virus infection and are sources of disease - causing soluble factors ( 6 ) . differences between dengue and influenza viruses in this regard , might result in different oas effects .
influenza viruses have not been shown to productively infect fcr - bearing immune cells or endothelial cells in humans ( 61 ) . however , inflammatory responses originating from virus - antibody - complement - complement receptor complexes on pulmonary endothelial cells and other fcr- and complement receptor - bearing myeloid lineage cells ( 5762 ) can not be ruled out .
conceptually , this situation could unfold anytime an optimal or protective ratio of antibody versus pathogen is disrupted by a rate increase in the number of pathogens that is higher than the rate of production of potentially protective cross - reactive or cognate antibodies ( 62 ) .
we might suggest the possibility of ' bad ' oas in the 1918 h1n1 pandemic , and likely in some cases of the p2009 h1n1 outbreak , based on insight from ' bad ' oas with the dengue virus . rapid virus replication could occur based on the unusually high virulence of the 1918 h1n1 virus ( 45 ) .
this would rapidly mobilize cross - reactive memory b cell responses in young adults , which were not sufficient for neutralization but still generated large amounts of immune complexes , with the rapidly replicating virus .
this , in combination with the reaction with complement - complement receptors on pulmonary endothelial cells and myeloid lineage cells such as macrophages and neutrophils , could have resulted in massive inflammatory responses .
reported symptoms of infection with the 1918 influenza virus suggest that this scenario was very likely ; autopsies and physician reports during the 1918 pandemic described symptoms of hemorrhagic tracheitis , bronchitis , and edematous hemorrhagic bronchopneumonia ( 53 ) .
this suggests that when an influenza virus replicates quickly , non - neutralizing cross - reactive antibodies generated from a memory response can potentially be more detrimental than the nave immune reaction ( 62 ) .
however , it is unreasonable to expect an immunocompetent adult to not have any oas against the influenza virus
. conceptually , the appearance of an unusually virulent , fast replicating influenza virus variant in a vaccine mismatch situation , could recapitulate disease severity seen in the 1918 pandemic in infected immunocompetent adults .
oas can be harnessed to defend against a pathogen , or a pathogen can harness oas to gain entry into the host cell through the mechanism of ade .
oas might also result in exaggerated inflammatory responses when there is disparity between the pathogen proliferation rate and the protective potential against the pathogen , which could be provided by cross - reactive memory b cells .
the normally protective cross - reactive memory b cell responses of oas being turned into ' self - destructive ' modes of immune complex formation with a pathogen , during ' battle ' against a fast replicating pathogen appears to be the inevitable casualties of the ' war ' between the human immune system and pathogens . from an evolutionary point of view
, mhc diversity in humans might represent a mobilization against such event ; but from the individual point of view , young adults who have an oas repertoire against influenza viruses , potentially through many natural infections and even without vaccination , could become casualties .
the possibility of recapitulating the disease severity of the 1918 pandemic exists , even if on a micro scale , as the influenza virus circulates every season .
therefore , sustained surveillance for identifying an unusually virulent influenza virus variant should be continued .
 the human immune system has evolved to fight against foreign pathogens . 
 it plays a central role in the body 's defense mechanism 
 . however , the immune memory geared to fight off a previously recognized pathogen , tends to remember an original form of the pathogen when a variant form subsequently invades . 
 this has been termed ' original antigenic sin ' . 
 this adverse immunological effect can alter vaccine effectiveness and sometimes cause enhanced pathogenicity or additional inflammatory responses , according to the type of pathogen and the circumstances of infection . here 
 we aim to give a simplified conceptual understanding of virus infection and original antigenic sin by comparing and contrasting the two examples of recurring infections such as influenza and dengue viruses in humans . 
ORIGINAL ANTIGENIC SIN
MECHANISM OF ORIGINAL ANTIGENIC SIN
ORIGINAL ANTIGENIC SIN AND VACCINE EFFICACY
ORIGINAL ANTIGENIC SIN AND INFLUENZA VIRUS IMMUNITY: 'GOOD' OAS?
CAN 'BAD' OAS PLAY A ROLE IN INFLUENZA VIRUS INFECTION?
ORIGINAL ANTIGENIC SIN AND DENGUE VIRUS INFECTION: CLASSIC 'BAD' OAS
CONCLUSION