The immunobiology of SARS-CoV-2 infection and vaccine responses: potential influences of cross-reactive memory responses and aging on efficacy and off-target effects

Abstract

Immune responses to both SARS-CoV-2 infection and its associated vaccines have been highly variable within the general population. The increasing evidence of long-lasting symptoms after resolution of infection, called post-acute sequelae of COVID-19 (PASC) or "Long COVID," suggests that immune-mediated mechanisms are at play. Closely related endemic common human coronaviruses (hCoV) can induce pre-existing and potentially cross-reactive immunity, which can then affect primary SARS-CoV-2 infection, as well as vaccination responses. The influence of pre-existing immunity from these hCoVs, as well as responses generated from original CoV2 strains or vaccines on the development of new high-affinity responses to CoV2 antigenic viral variants, needs to be better understood given the need for continuous vaccine adaptation and application in the population. Due in part to thymic involution, normal aging is associated with reduced naïve T cell compartments and impaired primary antigen responsiveness, resulting in a reliance on the pre-existing cross-reactive memory cell pool which may be of lower affinity, restricted in diversity, or of shorter duration. These effects can also be mediated by the presence of down-regulatory anti-idiotype responses which also increase in aging. Given the tremendous heterogeneity of clinical data, utilization of preclinical models offers the greatest ability to assess immune responses under a controlled setting. These models should now involve prior antigen/viral exposure combined with incorporation of modifying factors such as age on immune responses and effects. This will also allow for mechanistic dissection and understanding of the different immune pathways involved in both SARS-CoV-2 pathogen and potential vaccine responses over time and how pre-existing memory responses, including potential anti-idiotype responses, can affect efficacy as well as potential off-target effects in different tissues as well as modeling PASC.

Keywords: SARS-CoV-2; aging; anti-idiotype antibodies; immunology; vaccination.

Figure 1

Aging Predisposes to Pre-existing Memory Responses. During aging, there is marked shift towards long-lived memory T cells due to both the massive reduction of naïve T cell output from thymic involution and constant antigenic exposure throughout life. Some viral pathogens are endemic and continuous (hCoVs), while others (CMV, EBV) are latent and a also continual source of antigen exposure. The resulting in contraction of the T cell repertoire due to naive T cell loss and predominance of memory T populations results in an increasingly impaired ability to mount primary immune responses with age. Some of these pre-existing memory cells can also be cross-reactive to new viral pathogens such as SARS-CoV-2 depending on extent of antigen similarities and affinity of original response., These cross-reactive responses can then be both of lower affinity and duration. A similar propensity for pre-existing memory B cell responses also occurs with aging, working in concert with long-lived memory CD4+ T cell help.

Figure 2

Anti-idiotype Response and the Network Cascade. The induction of antigen-specific antibody responses results in polyclonal antibodies (Ab1). The immunogenic nature of the paratope (antigen-binding region) of Ab1 then can result in polyclonal anti-idiotype (Ab2) antibodies capable of binding and inhibiting Ab1 by forming complexes resulting in Ab1 clearance. The paratope of some of these Ab2 antibodies may be a “mirror” to the original antigen and then induce anti-anti-idiotype antibody responses (Ab3) which can then regulate the down-regulatory Ab2 but also some of which may have similar binding as the Ab1 to the original antigen and be protective. This cascade and effects may be contingent on the extent of immunization or antigen exposure as repeated immunizations can result in greater Ab2 responses as well as effects on aging where cross-reactive Ab2 may also affect initial Ab1 responses.

Figure 3

Molecular Mimicry and Potential Anti-Idiotype (Ab2)-Mediated Effects. Ab2 effects can be diverse and not limited to regulation of Ab1 responses. Ab2 are directed towards the Ab1 paratope or antigen- binding region and some can have their paratope be a mirror of the original antigen that is recognized. As such, these Ab2 can bind the same ligands the antigen which, in the case of SARS-CoV-2 infection or vaccination involving the Spike protein, can include the ACE2 receptor, resulting in multiple outcomes. If the Ab2 are antagonistic, they can competitively block ACE2 ligands from binding and inhibit function. The Ab2 upon binding can cause internalization thereby also being inhibitory. Some Ab2 could be agonistic and thereby stimulate ACE2 function. Finally, Ab2 binding ACE2+ cells can be targeted for attack by innate immune system due to ADCC (antibody-directed cell or complement-mediated cytotoxicity). A similar paradigm could exist with T cells, although this is much less characterized. Both inhibition and/or dysregulation of ACE2 function could result in potential pathology given critical role of ACE2 on multiple tissues/cells and in inflammation.

Figure 4

Choosing the Relevant Preclinical Models for CoV2: “Bench to Bedside Back to Bench”. Using young, inbred laboratory mice under SPF conditions fails to mirror the human landscape. Use of aged and obese mice, different strains, pregnant mice, mice that are prone to various autoimmune and disease states, and mice that have been exposed to various pathogens (including HCoV antigens) can all provide important insights. Studies in which repeated vaccinations, including heterologous, are applied and dissection of immune responses, including in different tissues, are assessed. These preclinical studies can then be linked with large animal models, such as non-human primate (NHP) using similar parameters as aging and obesity, which more faithfully represent human immune dynamics. The data can then be linked and validated with clinical results which then can drive questions using the various preclinical models on immune response efficacy and maintenance.