We have long considered immunological memory to be a hallmark of the so-called adaptive immunity, i.e. T and B cells, in that T and B cells, specific for a particular antigen, need to survive an encounter with that antigen and last in expanded numbers within our body in order to respond much more rapidly to a re-encounter with that same antigen compared to individuals who encounter that antigen for the first time.
At the outset, for reasons that will become clearer towards the end, I choose to differentiate immunological memory induced by an infection versus that induced by a vaccine. The latter are human contrivances, with the majority developed long before we understood anything about immunity. Importantly, we developed and approved for administration many if not most vaccines currently in use based on empirical evidence of efficacy, and we did so long before the current rigorous regulatory environment came into existence. The empirical nature of assessing efficacy means that we observed declines in population levels of certain infections targeted by vaccines without really understanding the mechanism(s) by which those vaccines work.
With the distinction between infection versus vaccine induced immunological memory front and center, let’s first look at the specific issues of immunological memory as it pertains to infections.
Issue #1. Adaptive immunity entails clonal selection and proliferation, concepts first explicated by. Upon encounter in a specific manner with an antigen that activates them, T and B cells specific for that antigen undergo clonal expansion and differentiate to become memory cells. Memory T and B cells can be generated throughout life but where to house their ever expanding numbers, given that space is finite within our body (1)?
Issue #2. Immunological memory is long lasting, maybe even lifelong. Immunologists typically rely on a few anecdotal examples as being emblematic of lifelong immunological memory.
A. Lifelong immunological memory to measles in the. There was a measles outbreak in this isolated Danish archipelago in 1781, and a second one 65 years later in 1846, with the islands apparently not visited by anyone in the intervening years. Panum was the King’s Royal surgeon sent to examine this second measles outbreak. In his careful report (2), he noted that Faroe islanders older than 64 years of age did not become ill, suggesting that they were protected by their prior exposure to the 1781 outbreak.
B. Sawyer (3) claimed in 1931 that anti-antibodies could be maintained for up to 75 years following infection.
C. Paul and colleagues (4) reported finding anti-antibodies in circulation in an isolated population of North Alaskans more than 40 years after exposure.
However, in each of these three examples, unexplored yet viable possibilities in maintaining long-term immunological memory are the roles of cross–reactive antigens and the expanded capacity of memory T cells to see antigen presented by many more cell types compared to naive T cells.
Issue #3. Does long-lasting immunological memory strictly require re-exposure to the original antigen that triggered the initial immune response or are periodic exposures to cross-reactive entities sufficient to re-activate and maintain immunological memory?
A. One of the most compelling examples demonstrating the potentially critical role of cross-reactivity in maintaining immunological memory comes from a well designed and thorough mouse model study published in 1998 by Raymond Welsh and colleagues (5). They performed serial infections of mice with heterologous, even unrelated viruses such as lymphocytic choriomeningitis (LCMV), Pichinde (PV), vaccinia (VV), and murine cytomegalo (MCMV) viruses, and showed that memory T cells specific to unrelated viruses contribute to the primary immune response to a second virus. How could this be? Aren’t the receptors (T Cell Receptors; TCRs) of T cells highly specific for particular peptide-MHC complexes? As Welsh and colleagues point out (5), “a single T cell clone can recognize two unrelated peptide sequences on the same protein, two different proteins of the same virus, and two different proteins from two unrelated viruses” (6, 7, 8).
B. More recently, in 2013, Mark M. Davis and colleagues (9) used more modern methodologies to show an abundance of expanded memory phenotype T cells specific for viral antigens in adults who, to their knowledge, had never been infected by those viruses. Like Welsh and colleagues, Davis et al also hypothesized that TCR cross-reactivity to environmental antigens helped explain the presence of these memory T cells in individuals not infected by these viruses. They too point out that alpha-beta TCRs expressed by CD4 and CD8 T cells have strong propensity for cross-reactivity to different peptide-MHCs (10, 11, 12).
refers to Issue #1 as akin to the problem faced by an old-school librarian with limited shelf space “who must decide whether to keep old, seldom-used texts or replace them with more current titles” (1). One way that our body appears to have resolved this “space” issue is to utilize the cross-reactive propensity of T and B cells to sort and maintain a memory pool. Within the finite space of our body, we intuitively understand that it is indeed more efficient to retain cross-reactive memory T and B cells since they could rapidly respond against more than one organism compared to memory T and B cells that were more specific for only one organism.
Let’s now take a look now at the specific issues of immunological memory as it pertains to vaccines.
The latecoined the phrase, “The Immunologists’ Dirty Little Secret” (13) to underscore the necessity for “dirt” to be present in order to initiate and maintain strong immune responses. Immunologists call this “dirt“ . Derived from the Latin word Adjuvare meaning help, Gaston Ramon apparently first coined this word in 1926 when he observed that horses inoculated with the diphtheria toxoid generated potent antitoxin sera if they also developed an abscess at the inoculation site (14). Adjuvants are thus defined as substances that when administered with an antigen induce greater immunity against it compared to the antigen alone.
The problem is that even today, we only understand bits and pieces of how immunological memory develops to an infection. We understand even less about what it takes for immunological memory to be long lasting. We use such incrementally gained knowledge to design new generations of more rationally designed vaccines.
In the meantime, over the course of the latter half of the 20th century till date, the regulatory environment for new vaccine approval has evolved towards an increasingly risk-averse stance with an emphasis on safety first. Thus, within such an onerous regulatory environment, we are caught in a classicsituation where newer vaccines need to be cleaner (safer) in order to gain regulatory approval yet in order for such vaccines to be truly effective in inducing long-lasting immunity (memory), they need to be “dirty“, i.e. adjuvanted.
One example that exemplifies this schism is in the case ofvaccines (15). The first generation of Pertussis Whole Cell vaccines (WCV) that contained killed bacteria were gradually replaced by the second generation of cleaner Acellular vaccines (ACV). Obviously different in composition, the “dirtier“ WCVs caused more adverse reactions (15). However, some recent studies (16, 17) also suggest that WCVs induce longer lasting immunity (memory) compared to ACV. In the meantime, coincident with increasing administration of the safer ACV vaccines, cases of Pertussis have been observed to steadily increase in countries such as Argentina, Australia, Canada, Finland, Norway, Spain, Switzerland, the Netherlands and the USA, all countries with successful and long-standing vaccination programs (18, 19, 20, 21, 22). We need to consider here that each vaccination program and each type of vaccine induces unique selection pressure(s) on the target organism in the wild. In the case of the pertussis, epidemiological data suggests an association between ACV and certain “escape” variants emerging within the vaccinated populations, variants that go on to cause disease. Thus, we may have to consider the possibility that cleaner vaccines may induce weaker immunity and weaker immunological memory, necessitating many booster shots over the course of a lifetime.
Finally, the issue ofis another important player in the case of vaccines. As populations become more comprehensively covered by vaccination programs, a natural corollary of is that carriage of certain organisms within an entire population is reduced. As a result, one could easily envisage that for an entity that is inherently less cross-reactive, its memory T and B cells might be less likely to get re-activated and maintained by cross–reactive environmental antigens. Further, under a variant of the , one could also easily envisage how lifestyles that limit exposure to such environmental cross-reactive antigens do their part in ensuring rapid waning of vaccine–induced immunity.
Another crucial difference between infection– and vaccine-induced acquired immunity ensues from their difference in routes. Most infections have typical “portals of entry“, namely, the mucosa (fecal-oral, nasal, vaginal) and skin, though some vector-borne infections (like malaria) can also directly access the blood. On the other hand, while the empirical nature of vaccine development does consider their capacity to induce immunity (immunogenicity), other aspects such as tradition, and vaccine safety and practicability are just as important. Such dueling demands dilute the imperative to mimic the infection route when developing vaccines. For example, the majority of inactivated vaccines are administered intra-muscularly even though I know of no infection that directly infects the skeletal muscle. Since over evolutionary time, infections honed their preferred routes, their typical “portals of entry“, it stands to reason that the sequence of events surrounding their entry would be a well orchestrated sequential dance that likely influences the nature and strength of the ensuing immunity, much of which is likely circumvented by a typical vaccine‘s route of administration. Vaccinologists/immunologists generally acknowledge that different routes of administration result in differences in immunity, and yet systematic human studies on such differences are sparse (23). Behind the types of injections used for vaccinations lie a combination of empiricism, tradition, cosmetic imperative and practicability, and not necessarily scientific rationale (24). An evidence-based approach such as examining how a given vaccination route influences the nature and strength of the ensuing acquired immunity would lead to improvement in vaccine performance.
2. Panum PL. Beobachtungen uber das Maserncontagium. Virch Arch 1847; 1:492.
3. Sawyer WA. Persistence of yellow fever immunity. J Prev Med 1931; 5:413-428.
4. Paul JR, Riordan JT, Melnick JL. Antibodies to three different antigenic types of poliomyelitis virus in
sera from north Alaskan Eskimos. Am J Hyg\U0010fc01\U0010fc06951; 54:275-285.
14. Annals de L’Institut Pasteur, 1926;40: 1 – 1 0