About Original Antigenic Sin...
About Original Antigenic Sin...
Part I: Elaborating on the Hypothesis
Going along with the UK Surveillance Data report people have been attributing the low anti-Nucleocapsid protein antibodies to a hypothesis called “Original Antigenic Sin” and postulating that those who have been previously vaccinated and then infected with SARS-COV2 are not producing N antibodies because their immune system was trained to target the spike and will neglect the other antigen.
I have had a really difficult time trying to create a post about this, mainly because the arena around OAS is absolutely a hot mess. It’s important to note that it’s a heavily debated topic, so even attributing OAS to something is a bit controversial because the evidence surrounding it is not concrete.
Be warned, I will be posting large blocks of texts taken from various studies. I want to make sure my readers examine these pieces and get a grasp of the context.
Let’s take a look at an OAS hypothesis in regards to SARS-COV2 and vaccination (from Brown et. al. 2021):
The speed and specificity of immunological memory are the basis of long-term, acquired immunity and of vaccinology. The power of memory, however, comes at a price. The cost? A memory response triggered to a similar but not identical array of antigens (e.g., a new exposure to a related but antigenically distant pathogen) can potentially be less effective than a response elicited in the absence of memory (1–4). This is possible because memory B cells producing antibodies of high affinity and specificity established following a primary exposure to one subset of antigens can prevent or significantly dampen responses by naive B cells to new antigens if they are part of a profile that includes antigens present during the primary exposure (5, 6). This is not a problem if the memory response produces neutralizing antibodies to antigens associated with the secondary exposure; however, problems do arise if memory B cells produce nonneutralizing antibodies to the antigens shared between primary and secondary exposures as reported recently in humans exposed to related human coronaviruses (hCoVs) and later infected with SARS-CoV-2 (7, 8). In such a scenario, not only can the memory response be ineffective, it can significantly attenuate the response of newly activated B cells that could have responded effectively to new antigens absent from the original priming event. The overwhelming response of memory B cells to cognate antigens that can hinder naive B cells of different and possibly neutralizing specificities from effectively responding to a new stimulus is known as the original antigenic sin (OAS), a biblical reference suggesting that the immune system is bound by the “sin” of its first imprinting to a target (1, 2). For example, people infected with H1N1 influenza viruses during childhood (and thus imprinted with that set of antigens/epitopes) were protected later in life against infections with a related virus such as H5N1 but not infections with more distantly related H3N2 (3, 9, 10).
So the idea with original antigenic sin is that the first exposure to a pathogen causes the immune system to focus on creating B cell memory based on that pathogenic strain, and the immune response to all subsequent exposure will be hampered so antibodies specific to the identical antigens of a different pathogen will not occur. It’s a mouthful, but the general idea is that your first exposure will shape all the immune response to all other exposures, possibly for the worse.
The authors also provided a schematic figure for other possible scenarios:
This schematic caused a lot of issues, mainly for the (B) portion, and I’ll admit I kept getting caught up in this figure.
In this hypothetical scenario the authors propose what may happen if someone who had previous exposure to a coronavirus then gets exposed to SARS-COV2. The big area of concern here is (B). In this scenario, both a previously circulating coronavirus strain and SARS-COV2 share a similar antigen (similar, not the same)- let’s say a spike protein.
The idea proposed is that if the antibodies produced against this antigen (Green) for SARS-COV2 are not neutralizing, it may not protect against the infection. What would be even more concerning is if this prior memory hinders the immune system’s ability to spot new antigens (let’s say Nucleocapsid proteins) and mount an immune response to that because it is already tied up with the spike protein.
If this hypothesis were to be true it would absolutely match what we see with the UK Surveillance data; people vaccinated produce anti-spike antibodies, and when they are infected their immune systems will be tied up with targeting the spike and they will not mount a strong immune response to the N protein.
If we can find any evidence in the literature to validate this position, maybe we can justify what we see with the UK Surveillance Data, but like I said this arena is a hot mess.
One of the biggest challenges is that, in the case of SARS-COV2 vaccination then infection, we need to look at a scenario where vaccination with only one antigen causes the shunting of an immune response against all other antigens of a virus, and there doesn’t seem to be any evidence of this in the literature.
The authors used Gardasil vaccinations as an example of OAS, indicating that vaccination with Gardasil (which contains 4 human papillomavirus strains) caused reduced immune responses to the 5 new HPV strains in a Gardasil 9 vaccine. However, if we look at the package insert we can see that each vaccine contains the viral capsid protein (L1), and not the whole virus.
So in this case we are looking at previous exposure to an antigen causing the inhibition of subsequent exposure to similar antigens.
But what about the flu? Influenza vaccination is used as an example of OAS occurring, but once again this doesn’t apply to our scenario since most flu vaccines are either attenuated or inactivated whole viruses. Even then, the arena seems to be extremely spotty as well.
Here’s an excerpt from Smith et. al. 1999:
Influenza vaccination works effectively in first-time vaccinees (2). However, efficacy in repeat vaccinees has been difficult to determine definitively. A meta-analysis of 19 repeat vaccination studies showed that on average repeat vaccinees were protected at least as well as first-time vaccinees (3). However, in the 12 studies in which protection was measured serologically, there was statistically significant unexplained heterogeneity: In some years repeat vaccinees were better protected than first-time vaccinees; in other years they had worse protection (3). Similarly, two widely cited vaccine efficacy field studies have reached different conclusions: The “Hoskins study” (4) concluded that repeat vaccination was not effective, whereas the “Keitel study” (5) concluded that repeat vaccination was effective. There was also heterogeneity within the Hoskins (6) and Keitel studies (Fig. (Fig.1).1). Meta-analysis found no factor that explained the heterogeneity among 12 serological studies; among the factors tested were differences in influenza subtype, age, study design, hemagglutination inhibition (HI) assay method, and vaccine type (3).
However, the Smith et. al. study does point to something important. In this study computer modeling was used to examine the discrepancy seen between vaccinations and immune response. The researchers suggest that this may be due to antigenic distance- the more dissimilar antigens are the less likely the immune system is to mount a previous B memory response against the new antigen, and would thus mount a new immune response specific to the newly presented antigen.
Taken from the Discussion section:
Our results show that antigenic distances between the first and second vaccines, and between the first vaccine and the epidemic strain, significantly affect attack rates in repeat vaccinees. The model accurately predicted vaccine efficacy in repeat vaccinees, relative to that in first-time vaccinees, for outbreaks during Hoskins and Keitel studies of annual influenza vaccination (Figs. (Figs.11 and and5).5). Thus, the proposed antigenic distance hypothesis offers a parsimonious explanation for the differing observations in the Hoskins and Keitel studies.
In repeat vaccinees, when the v1–v2[vaccine1 - vaccine2] distance was small, antibodies produced by the immune response to v1 cross-reacted with v2, eliminating some of v2 before it induced an immune response—a phenomenon we call negative interference. When the v1–e [vaccine1 – epidemic virus] distance was small, antibodies produced by the response to v1 cross-reacted with the epidemic strain and helped clear it—a phenomenon we call positive interference by v1 on the epidemic virus. Thus, attack rates varied in repeat vaccinees depending on the combination of negative and positive interference induced by v1, which in turn depended on the v1–v2 and v1–e distances, respectively. Positive and negative interference are well documented aspects of the cross-reactive immune response (8, 9); in this study we have combined them in a quantitative way to predict vaccine efficacies in first-time and repeat vaccinees.
This is going to be an important concept to keep in mind: if antigens of vaccines are too similar, the body may use memory B cells to mount an immune response instead of relying on naïve B cells and training them to specifically target the new antigens. In the case of vaccination, it would indicate that exposure to a new vaccine will cause the body to activate previously matured memory B cells to target the vaccine, and if it can properly eliminate the vaccine without mounting a new immune response by new B cell maturation it will find no need to, and no immune specificity to the new vaccine will be produced.
The confusion among OAS is reiterated in a 2017 paper by Monto et. al. Which highlights that many attributions to OAS may be incorrect. I suggest people read this paper (really all of these papers to be frank).
I’ll highlight a point made about the 2009 H1N1 flu epidemic (apparently copying and pasting from a document removed the citations so check the paper for those):
Only rarely was the actual concept of OAS with immunologic imprinting considered in the late 20th century, even after the return of the A(H1N1) viruses in 1977, when those >25 years of age were largely protected []. An exception was the work of Powers and Belshe, who, in studying an older population, sought to separate the effects of aging and OAS on immune response []; they were interpreting OAS to mean a possible reduction in antibody response to new viruses among individuals first exposed to older viruses. They examined rises in antibody titer to the original A(H1N1) variants, ASw and A0, after receipt of 1990–1991 seasonal vaccine and their relation to the ages of the individuals involved. Older individuals had smaller responses than younger individuals overall, but both age groups had better responses to newer viruses than to older viruses. Thus, OAS was not responsible for a reduced antibody response in older persons and the problem was attributed to immune senescence.
Pandemics are generally associated with a revisiting and reexamination of prior concepts. The 2009 A(H1N1) pandemic was no exception. Unlike the situation in 1977, the evidence of overall protection among older individuals was recognized in the context of the effects of prior infection with older A(H1N1) viruses. A commentary entitled “The Wages of Original Antigenic Sin” was written in response to a letter entitled “Original Antigenic Sin and Pandemic (H1N1) 2009” [, ]. As in 1977, nearly all older individuals who had lived through the previous period of A(H1N1) virus circulation were protected [, , ]. Response to the 2009 monovalent vaccine was good in all age groups, even in those that did not previously have experience with older strains of A(H1N1) []. A possible exception, cited in several reports, was that those who had previously received seasonal A(H1N1)-containing vaccines had reduced antibody responses to the pandemic vaccine, a phenomenon that also was referred to by the authors as a version of OAS but clearly involved negative antigenic interaction, rather than imprinting [].
This reiterates the point made by Smith et. al. : prior vaccination may affect subsequent vaccinations of similar viral strains because the body will utilize memory B cells it already has to eliminate the new vaccine instead of mounting a new response.
But once again we are still left wanting. We still don’t have evidence of an OAS scenario that fits our situation. Regardless, we are building up plenty of evidence to other possible scenarios.
But before we examine our SARS-COV2 predicament let’s look at a study by Kim et. al. 2009 in which researchers reexamined the original study that proposed Original Antigenic Sin.
Most immune responses follow Burnet’s rule in that Ag recruits specific lymphocytes from a large repertoire and induces them to proliferate and differentiate into effector cells. However, the phenomenon of “original antigenic sin” stands out as a paradox to Burnet’s rule of B cell engagement. Humans, upon infection with a novel influenza strain, produce Abs against older viral strains at the expense of responses to novel, protective antigenic determinants. This exacerbates the severity of the current infection. This blind spot of the immune system and the redirection of responses to the “original Ag” rather than to novel epitopes were described fifty years ago. Recent reports have questioned the existence of this phenomenon. Hence, we revisited this issue to determine the extent to which original antigenic sin is induced by variant influenza viruses. Using two related strains of influenza A virus, we show that original antigenic sin leads to a significant decrease in development of protective immunity and recall responses to the second virus. In addition, we show that sequential infection of mice with two live influenza virus strains leads to almost exclusive Ab responses to the first viral strain, suggesting that original antigenic sin could be a potential strategy by which variant influenza viruses subvert the immune system.
Protection against influenza viruses is mediated primarily by neutralizing Abs (9, 10). The host responds to the viral infection by generating lifelong memory cells and neutralizing Abs and the viruses adapt and evolve via antigenic drift. This generates variant viruses that can no longer be neutralized by previous Abs (11). As a result, the variant viruses maintain shared epitopes with the parental strain but also have unique epitopes that allow escape from neutralizing Abs. When an immune host is exposed to this variant influenza virus, two things need to happen to ensure a successful protection: 1) activation of memory B cells that recognize shared epitopes and 2) activation of naive B cells that recognize novel epitopes. In the case of repeated infection with variant influenza viruses, the latter response is not induced and this phenomenon is called original antigenic sin. Original antigenic sin was first discovered ∼5 decades ago by Thomas Francis Jr. and several others (12, 13, 14). Natural infection in humans with antigenically drifted strains of virus induced Ab production against their childhood strains, but response against the current strain was severely diminished (15). Original antigenic sin is not unique to humans as other studies have reported similar observations in various animal models including mice, ferrets, and rabbits (16, 17, 18, 19).
Despite this evidence established in humans as well as lower species, there is still controversy over whether original antigenic sin is a real phenomenon associated with influenza vaccines or infection. Recent studies have raised questions about the existence of original antigenic sin. Gullati et al. (20, 21) showed that immunization of humans with influenza vaccines indicated little evidence of original antigenic sin. In addition, a recent elegant study by Wilson and colleagues (21) showed that the most of the human serum Abs following vaccination bound to the current vaccine strain with greater affinity than to the previous vaccine strain, suggesting insignificant interference of original antigenic sin.
What’s great about this study is that the researchers compared 3 different scenarios to see if OAS would occur. They used a DNA-based vaccine that encoded the hemagluttinin protein (HA) of influenza viruses, an inactivated influenza virus vaccine, and also used mice-adapted live influenza viruses. So let’s examine their results:
For our study, we chose the two related H1N1 strains, PR8 and FM1, which were the same ones analyzed by Virelizier and colleagues in the 1970s (16, 17). We cloned and sequenced the HAs from the two strains and found that they exhibited 92% identity at the amino acid level (data not shown). Interestingly, most of the changes in HA from FM1 mapped to Ab neutralization sites in HA from PR8, suggesting strong selective pressure on the FM1 virus to render it less susceptible to anti-PR8 Abs (data not shown). We sequentially immunized mice with HA-encoding DNA vaccines or whole formalin-inactivated viruses and observed that the Ab response in PR8-primed and FM1-immunized mice was oriented toward the original Ag (PR8), while the Abs to immunizing Ag (FM1) were reduced (Figs. 1⇑ and 2⇑, A and B). Our data are in agreement with studies done by Schild and colleagues (16) who showed that sequential immunization with purified HAs from two related influenza viruses led to original antigenic sin. These viruses shared cross-reacting antigenic determinants but differed in strain-specific antigenic epitopes. Immunizing mice first with H0 HA (later identified as H1N1) and 2 mo later challenging with homologous (H0), cross-reacting (H1), or unrelated H3 HA proteins led to strong Ab responses to the “original” H0 HA. We also observed that FM1-specific HAI and neutralization titers increased with time and there was a delayed development of FM1 strain-specific responses at later time points (data not shown). These observations conform to the findings by Webster and colleagues (19) who, using Ag adsorption methods, demonstrated the generation of strain-specific responses at later time points.
In contrast to the induction of original antigenic sin by immunization with HA-encoding DNA vaccines, sequential immunization of mice with formalin-inactivated PR8 and FM1 viruses did not show overt evidence for original antigenic sin. The HAI titers and neutralization titers induced against the original Ag, PR8, were only 2–3-fold higher than titers against FM1 at days 7, 14, and 28 following FM1 immunization. These differences, for the most part, were statistically insignificant, indicating that B cell responses to the original Ag as well as the immunizing Ag were generated. This could explain why Wrammert and colleagues (21) found little evidence for original antigenic sin in humans immunized with inactivated influenza virus vaccines. They showed that the interference of original antigenic sin was insignificant in the human Ab response to various vaccine strains. Using human recombinant mAbs generated from sorted single Ab secreting cells, they showed that most recombinant mAbs bound the current vaccine strain with equal or greater affinity than the previous vaccine strain, despite a 10% or less difference of the HA sequence of the current vs previous vaccine strains. Thus, vaccination with inactivated viruses shows minimal evidence of original antigenic sin. Surprisingly, however, despite these minimal differences in serum neutralization as well as HAI titers, these mice were clearly compromised in generating memory responses. When mice sequentially immunized with inactivated PR8 and FM1 were challenged with 100 × LD50 live mouse-adapted FM1 virus, they had 46-fold higher (p = 0.007) viral titer in their lungs than mice immunized with inactivated FM1 virus only (Fig. 1⇑C). Thus, even though the effects of original antigenic sin were minimal in mice sequentially immunized with whole, inactivated viruses, there was a deficit in the establishment of the memory pool and the ability of these animals to respond to subsequent live viral challenge.
Interestingly, in mice sequentially infected with live mouse-adapted influenza viruses, the induction of original antigenic sin was much more profound (Fig. 3⇑, A and B). Sequential infection with live viruses generated severely reduced neutralization Ab responses and compromised memory responses to the second virus. Upon challenge with 100 × LD50 live FM1 virus, these mice exhibited 4 logs higher viral titers in the lungs than mice infected with FM1 virus only (Fig. 3⇑C). The induction of original antigenic sin was not dependent upon the dose of viruses (0.01 or 0.1 LD50) (data not shown) or the order in which the viruses were administered as reversing the order of infection, FM1 followed by PR8, induced preferential Ab production directed toward the original Ag, FM1 (Fig. 6⇑). These data suggest that variant influenza viruses might use original antigenic sin as a potential mode to escape from the host immune system. How live viruses accomplish this while inactivated viruses do not is not entirely clear. It is partially due to neutralization of the second virus, FM1, by pre-existing PR8 Abs, resulting in lower antigenic load (Fig. 4⇑). However, it remains unclear whether this cross-neutralization and lowering antigenic load plays a role in mice sequentially immunized with whole, inactivated viruses. The key difference might presumably be the varying degrees of engagement of the innate arm of the immune system by live vs formalin-inactivated viruses (27, 28). Thus, the success of influenza virus’ prevalence stems from the ease of host-to-host transmission, susceptibility to mutational shift/drift and induction of original antigenic sin to escape from the host immune system.
This study outlines something very important: it indicates that the type of vaccine administered (and in turn, the type of virus/antigen) matters. In this case antigen-specific vaccines lead to large scale OAS while the use of inactivated viruses did not. Interestingly, sequential exposure with live viruses lead to OAS, but in this case it may be the fault of the flu virus’ ability to escape the immune system more than direct OAS occurring.
From there, we’ve laid some of the basics to explain Original Antigenic Sin. In the next post I’ll indicate a minor correction to my previous post about the UK Surveillance Data. We’ll then see if we can utilize OAS to explain some of the phenomena, then hypothesize how we can go about examining this.