Saturday, December 21, 2019

PLoS Path.: Childhood Immune Imprinting to Influenza A


Credit NIAID











#14,593

One of the stock assertions regarding influenza A - which I used only yesterday - is that A/H3N2 tends to impact adults over 65 the most severely, while A/H1N1 typically has its biggest impact on younger adults. 
This was something we saw quite prominently during the 2009 H1N1 pandemic, when those over the age of 50 were less harshly impacted than younger cohorts.  Those born between 1918 and 1957 - when H1N1 was the only influenza A in circulation - fared much better than those born after 1957, the year that H2N2 emerged (followed by H3N2 in 1968).
In 2010's  EID Journal: Original Antigenic Sin And Pandemic H1N1we looked at a  highly plausible explanation; that the first flu subtype you are exposed to in life creates a lasting impression on your immune system. 
Original Antigenic Sin (OAS) is a term coined in 1960 by Thomas Francis, Jr. in the article On the Doctrine of Original Antigenic Sin) that postulates that when the body’s immune system is exposed to and develops an immunological memory to one virus, it may be less able to mount a defense against a subsequent exposure to a second slightly different version of the virus.
In 1977, H1N1 returned (under mysterious circumstances) after a 20 year absence and sparked a pseudo-pandemic, primarily affecting those under the age of 20.
In previous pandemics (1918, 1957, 1968) the newly arrived subtype quickly supplanted the old one, but this time - perhaps because it impacted a relatively small subset of the population  - H1N1 began to co-circulate with H3N2 instead of replacing it. 
Prior to 1977, it was pretty easy to determine what influenza A subtype a person was first exposed to (excluding those born just prior to or during a pandemic year), but since then the waters have been muddied considerably.

While lasting immunity from your first flu exposure makes sense, we've also seen patterns of infections in novel flu viruses like H5N1 and H7N9 -  subtypes which haven't circulated widely - producing similar age shifts.  H5N1 tends to infect children and young adults, while H7N9 prefers older hosts (see H7N9: The Riddle Of The Ages).

Three years ago, in Science: Protection Against Novel Flu Subtypes Via Childhood HA Imprinting, we looked at new research which suggested the influenza HA Group type you are first exposed to also makes a significant, and lasting, impression on your immune system. 


And that the resultant immune response may carry over to other - similarly grouped - subtypes.

While more theoretical than proven, this suggests if your first influenza exposure was to H1N1 or H2N2 (group1), you may carry some degree of immunity to the H5 viruses (H5N1, H5N6, etc.), while if your first exposure was to H3N2 (group 2), you may carry some protection against H7 viruses instead (see Nature: Declan Butler On How Your First Bout Of Flu Leaves A Lasting Impression).

While all of this seems a simple and elegant explanation, in January of 2018, in mBio: Pandemic Paradox - Early Life H2N2 Infection Enhanced Mortality From H1N1pdm09, we saw a study finding those born during the 1957 H2N2 pandemic saw the highest mortality in 2009 (see mbio chart below).



This was doubly unexpected. 

H1N1 and H2N2 are both group 1 HA types, and some cross protection might be expected. Also, the mortality rate dropped for those born after 1957 - when H2N2 was still circulating - and didn't spike for those born during the 1968 pandemic when H3N2 (a group 2 HA type) was the only influenza A game in town.
Elegant or not, there is obviously more to all of this than we currently understand.  
Moving us a bit further down the line however, today we've a study published yesterday in PloS Pathogens, that takes another look at the impact from early childhood imprinting from a specific HA Subtype, as well as that subtype group

This is a lengthy and detailed report, and one that will require a fair amount of time to read and digest.  There is a synopsis, in the form of a press release from the University of Arizona (Why your first battle with flu matters most), that covers the highlights, and is worth reading first.

The link to the full open-access paper, and abstract, follow.  I'll have a brief postscript when you return.

Childhood immune imprinting to influenza A shapes birth year-specific risk during seasonal H1N1 and H3N2 epidemics
Katelyn M. Gostic , Rebecca Bridge, Shane Brady, Cécile Viboud, Michael Worobey, James O. Lloyd-Smith

Published: December 19, 2019
https://doi.org/10.1371/journal.ppat.1008109
Abstract
Across decades of co-circulation in humans, influenza A subtypes H1N1 and H3N2 have caused seasonal epidemics characterized by different age distributions of cases and mortality. H3N2 causes the majority of severe, clinically attended cases in high-risk elderly cohorts, and the majority of overall deaths, whereas H1N1 causes fewer deaths overall, and cases shifted towards young and middle-aged adults. These contrasting age profiles may result from differences in childhood imprinting to H1N1 and H3N2 or from differences in evolutionary rate between subtypes.
Here we analyze a large epidemiological surveillance dataset to test whether childhood immune imprinting shapes seasonal influenza epidemiology, and if so, whether it acts primarily via homosubtypic immune memory or via broader, heterosubtypic memory. We also test the impact of evolutionary differences between influenza subtypes on age distributions of cases. Likelihood-based model comparison shows that narrow, within-subtype imprinting shapes seasonal influenza risk alongside age-specific risk factors. The data do not support a strong effect of evolutionary rate, or of broadly protective imprinting that acts across subtypes.
Our findings emphasize that childhood exposures can imprint a lifelong immunological bias toward particular influenza subtypes, and that these cohort-specific biases shape epidemic age distributions. As a consequence, newer and less “senior” antibody responses acquired later in life do not provide the same strength of protection as responses imprinted in childhood. Finally, we project that the relatively low mortality burden of H1N1 may increase in the coming decades, as cohorts that lack H1N1-specific imprinting eventually reach old age.
Author summary
Influenza viruses of subtype H1N1 and H3N2 both cause seasonal epidemics in humans, but with different age-specific impacts. H3N2 causes a greater proportion of cases in older adults than H1N1, and more deaths overall. People tend to gain the strongest immune memory of influenza viruses encountered in childhood, and so differences in H1N1 and H3N2’s age-specific impacts may reflect that individuals born in different eras of influenza circulation have been imprinted with different immunological risk profiles.
Another idea is that H3N2 may be more able to infect immunologically experienced adults because it evolves slightly faster than H1N1 and can more quickly escape immune memory. We analyzed a large epidemiological data set and found that birth year-specific differences in childhood immune imprinting, not differences in evolutionary rate, explain differences in H1N1 and H3N2’s age-specific impacts.
These results can help epidemiologists understand how epidemic risk from specific influenza subtypes is distributed across the population and predict how population risk may shift as differently imprinted birth years grow older. Further, these results provide immunological clues to which facets of immune memory become biased in childhood, and then later play a strong role in protection during seasonal influenza epidemics.
          (SNIP)
Altogether, this analysis confirms that the epidemiological burden of H1N1 and H3N2 is shaped by cohort-specific differences in childhood imprinting [9,12,13,16,54], and that this imprinting acts at the HA or NA subtype level against seasonal influenza [16,17].
The lack of support for broader, HA group-level imprinting effects emphasizes the consequences of immunodominance of influenza’s most variable epitopes, and the difficulty of deploying broadly protective memory B cell responses against familiar, seasonal strains. Overall, these findings advance our understanding of how antigenic seniority shapes cohort-specific risk during epidemics.
The fact that elderly cohorts show relatively weak immune protection against H3N2, even after living through decades of seasonal exposure to or vaccination against H3N2, suggests that antibody responses acquired in adulthood do not provide the same strength or durability of immune protection as responses primed in childhood.
Immunological experiments that consider multiple viral exposures, and cohort studies in which individual histories of influenza infection are tracked from birth, promise to illuminate how B cell and T cell memory develop across a series of early life exposures.
In particular, these studies may provide clearer insights than epidemiological data into which influenza antigens, epitopes and immune effectors play the greatest role in immune imprinting, and how quickly subtype-specific biases become entrenched across the first or the first few exposures.
         (Continue . . . )

While the impacts of childhood immune imprinting by flu viruses are becoming better understood, the mechanics behind it remain largely unknown, and understanding those may be key in order to deliver a truly universal flu vaccine. 
Issues surrounding OAS and ADE (Antigenic Dependent Enhancement) affect more than just influenza, and appear to have played a role in 2017's Dengue vaccine debacle (see Philippines: FDA Withdraws Dengvaxia® Vaccine - Sanofi Quantifies Risk), and may influence the impact of other vectorborne diseases (PLoS Currents: Another In Vitro Study Suggests Previous Dengue Exposure May Exacerbate Zika Severity).
What we are learning is that the human immune response is far more complex than we ever imagined, and the constantly-evolving antigenic face of influenza - along with the changing immune demographics of an aging population - add even more layers of complexity.

There's still a long road ahead, but we are considerably closer to answers than we were a decade ago.