Part 1. Nature Of Acquired Immune Responses, Epitope Specificity And Resultant Protection From SARS-CoV-2
Apr 17, 2023
Abstract
The major global response to the SARS-CoV-2 pandemic has been to bring to the clinic as soon as possible a number of vaccines that are expected to enhance immunity to this viral infection. While the rapid development and testing of these vaccines (at least in terms of short-term efficacy and safety) is commendable, it should be acknowledged that this has occurred despite the lack of research and understanding of the important immune elements of natural host resistance to the virus, which makes this effort somewhat unique in medical history. Conversely, as the following review points out, there have been important observations in the past that suggest that respiratory infections on mucosal surfaces are susceptible to immune clearance mechanisms that are not typical of infections caused by systemic (blood-borne) pathogens. Therefore, it may be important to understand the role of innate and acquired immunity in response to viral infections and the optimal acquired immune resistance mechanisms (B-cell or antibody-mediated, versus T-cell-mediated) for viral clearance. This information is needed to guide vaccine development and monitor vaccine success. We already know that many pathogens enter into a quasi-symbiotic relationship with their hosts, with each pathogen undergoing successive changes in response to changes in its presence by another pathogen. The subsequent evolution of viral variants as host immunity has developed over the past 3-6 months is a completely predictable response, which has caused widespread concern. What is unclear is whether the use of novel vaccines in humans will produce other, as yet unidentified, unintended side effects, and if so, how and whether these side effects can be avoided. We conclude by stating that it is a poor practice to ignore a large body of well-documented immunological studies for the sake of expediency.
Keywords
SARS-CoV-2; host resistance; innate immunity; acquired immunity; mucosal immunity; vaccination; Cistanche benefits.
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Introduction
In the past 18 months, the world has suffered the ravages of a pandemic caused by a coronavirus infection originating in Wuhan, China, in late 2019. By mid-2020, there was clearly a global consensus that the way to address the socioeconomic and medical dilemma was to rapidly develop and implement a universal vaccination program. However, unlike past precedents, this is occurring in the context of a relative lack of detailed knowledge and investigation of the natural nature of host resistance to the pathogen in question, and in the context of "fast-tracking" the design of new vaccines to clinical use, again in the absence of detailed knowledge of the likely short- and long-term effects of such vaccine administration. The same lack of detailed knowledge of the likely short- and long-term effects of such vaccine administration. In a recent review, the (then) current state of understanding of SARS-CoV-2 immunization and how this may affect future protective vaccination approaches was discussed. One concern raised in that review was that too little effort has been invested in understanding the nature of the immune response that may provide optimal immune protection. The following is an analysis of the progress that has been made to improve this understanding and how and if these advances have influenced the global response to the SARS - COV - 2 pandemic and may further influence it.
Mammalian immunity has both innate and adaptive aspects. Innate immunity is the only immune mechanism that develops rapidly (1-2 days) in 95% of species on Earth, and some evidence also suggests immune memory, "training enhances protection against reinfection (with the same pathogen) and even enhances immunity against novel pathogens. This new idea suggests a closer link to adaptive immunity, long thought to be the only immune system that displays memory.
Figure 1 shows the causal relationship between deaminase mutagenic activity, SARS-COV-2 infection, the role of the interferon-stimulated gene (ISG) pathway, the host innate and adaptive immune response, and the subsequent possible accumulation of collateral cell damage. Innate immunity involving deaminases aims to suppress pathogens through MUL. tiple, mostly non-genetic pathways. Genetic targeting of the SARs-Cov-2 RNA genome by deaminases, i.e., mutations in the pathogen genome induced by innate immunity, affects its replication effect. The deaminases APOBEC3B and APOBEC3Gin have been studied for 20 years and are now commonly referred to as "virus crushers" because They have well-characterized mechanisms to affect viral potency and function. This is the first line of innate immune defense to suppress or eliminate the SARS-CoV-2 virus. During the ISG-induced deaminase attack on foreign pathogens, some uncorrected de novo mutations may also accumulate in the transcribed non-g-gene DNA and may lead to further cellular damage in infected tissues.
Figure 1. A model linking downstream innate and adaptive immune changes following pathogen insult.
The mechanisms involved in innate immune training may involve epigenetic changes (altered DNA methylation; histone deacetylase activity) that lead to more rapid activation of genes associated with pathogen response. Epigenetic chemical alterations in gene parts constitute part or all of the genetic regions that may be targets for deamination during transcription. Conversely, it is plausible that those regions that are chemically protected from deamination are conserved, where DNA fidelity needs to be maintained to sustain biological survival and normal function. In a landmark study by Guo et al., the TET1 gene and the oncogenic adenosine deaminase APOBEC1 were found to be actively involved in DNA methylation changes induced by region-specific neuronal activity. The concept of innate immune response training may help to explain, to some extent, the lower infant mortality and even adult mortality in the same population vaccinated with BCG (BCG mixed with adjuvant is an excellent inducer of the innate immune response) than in the non-BCG vaccinated population. In vaccine development, BCG-mediated innate immune training was the underlying principle of the ACTIVATE trial in elderly volunteers, which was designed to assess the contribution of BCG in reducing susceptibility to bacterial diseases and, more recently, SARS-CoV-2 infection.
Innate and acquired immune deficiencies are particularly evident in the elderly. Innate immunity rapidly controls viral replication in infected healthy subjects through type I and type III interferon-induced antiviral immunity. Elderly patients lacking this rapid innate response are at very high risk for serious outcomes following SARS-CoV-2 infection, including increased morbidity and mortality. type 1 and type III interferon-inducible genes include APOBEC and ADAR-inducible expression, as described in Figure 1 and elsewhere, and they can in turn be expressed in SARS-COV-2-expressing genes of "haplotype switching", which in turn leads to a diversification of viral inheritance patterns, as seen in some subjects, but especially in people with impaired innate immunity (see below).
Adaptive (acquired) T and B lymphocyte-mediated immunity, while certainly primarily responsible for immune memory, does not become active until approximately 10-14 days after pathogen exposure, but typically exhibits greater pathogen recognition diversity than innate immunity. Given the experience in understanding how acquired immunity mechanisms can be exerted through intentional vaccination to enhance pathogen resistance, and the numerous successes in global disease control reported as a result, it is not surprising that this strategy has been used as a key strategy in the past 12-18 months of efforts to address the current pandemic. The following discussion reviews what we have learned about the importance of antibody (B cell-mediated) and T-effect immunity in providing protection after natural infection or vaccination, and how pathogens in turn respond to naturally acquired or vaccine-induced increases in host resistance. In addition, a brief overview of some of the unexpected adverse effects that have been noted with current "working" vaccines and how this may influence the future direction of vaccinology will be presented.
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1. Heterogeneity in SARS-CoV-2 Antibody Responses and SARS-CoV-2 Protection
Early studies of virus entry into the cells of infected individuals showed that virus entry is dependent on the receptor-binding structural domain (RBD) of the spike (S) protein of SARS-CoV-2. Thus, many studies on naturally infected and even vaccinated individuals have focused on the epitopes (different unique antigenic configurations) of the RBD recognized by antibodies (see below, T cells). Despite lower virus-neutralizing titers after natural infection and recovery, commonality in Ig responses to various RBD structural domains in S proteins was found in recovered individuals. Notably, independent analyses of naturally infected COVID subjects showed a very weak correlation between antibody titers and neutralizing activity in sera measured using commercial clinical laboratories. This is perhaps not surprising, as an independent study looked at various B-cell subsets that produce antigen-specific Ig responses following SARS-CoV-2 infection. This group reported that B cells could be segregated into discrete functional subpopulations specific for spike-in (S), nucleocapsid (NP), and open reading frame (ORF) proteins (consistently named, 7a and 8), but only S-specific B cells were enriched in memory B cell clusters and monoclonal antibodies (mAbs) from these cells were efficiently neutralized. In contrast, ORF8 and NP-specific B cells were enriched in naive and innate-like clusters, and monoclonal antibodies against these targets were not neutralized. Again, serum Ig binding on the viral antigen and antibody platforms of 15 SARS-CoV-2 positive and 30 negative controls were studied and then assessed for viral neutralization, and S-IgG3 was reported to provide the highest accuracy in predicting viral neutralizing activity in serologically positive individuals.
Recent analyses of epitope binding have highlighted the complexity of dissecting Ig responses to the RBD to assess protective effects. 38 RBD-binding neutralizing antibodies with known structures, mostly isolated from virally infected patients, were grouped into five general clusters that, in turn, were able to record different non-neutralizing surfaces on the RBD. These neutralizing antibodies can bind to the RBD at most simultaneously, which has important implications for vaccine design. These clinical analyses emphasize the importance of the response to the RBD in the S protein in protection, which in turn is supported by independent data from animal model studies. Following a high-dose SARS-CoV-2 attack in Syrian hamsters, the passive transfer of potent neutralizing antibodies (nAbs) to two epitopes on the RBD of the S protein receptor binding domain provided protection against disease by maintaining body weight and low lung virus titer monitoring. In addition, immunization of mice with recombinant poxvirus expressing a modified SARS-CoV-2- s protein (which is recognized by anti-rbd Ig and soluble human ACE2 receptor on virus-infected cells) produced neutralizing Ig that passively protected transgenic human ACE2 mice from lethal SARS-CoV-2 infection. Transgenic mice immunized with cowpox vectors inoculated prior to infection with neo-coronavirus showed no morbidity or weight loss after intranasal infection with neo-coronavirus at either 3 weeks or 7 weeks. In addition, no infectious SARS-CoV-2 or subgenomic viral mRNA was detected in the lungs. in addition, induction of cytokines and chemokines mRNA was reported to be greatly reduced, and small levels of virus were found in the nasal turbinates of 1/8 rMVA-vaccinated mice on day 2 (and none thereafter).
Despite these data, it should be acknowledged that SARS-CoV-2 infection in children does not have the same clinical presentation and does not produce the same immune response after infection. Children are largely spared from severe respiratory disease but may develop a multisystem inflammatory syndrome similar to Kawasaki disease. The diversity and specificity of SARS-CoV-2-specific Igs are lower in children compared to adults, and both children and adults produce IgG, IgM, and IgA Abs against S proteins, but only adults produce significant responses to nuclear capsid (N) proteins. Children produced significantly lower neutralizing activity compared to the SARS-CoV-2-infected adult cohort. No data are available on the relative response of the two cohorts to vaccination.
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2. The Role of Mucosal Immunity in Protection against SARS-CoV-2
It has been known for many years that the best form of protective immunity against pathogens invading by the nasal or oral route is the local secretory IgA response. Recent analyses of SARS-CoV-2 reinfection and transmission in vaccinated individuals and studies evaluating influenza and SARS-CoV-2 immunization are consistent with this concept. Froberg et al. reported that mucosal IgA responses were detected in cases of natural infection without a serum antibody response, in which case mucosal antibody levels correlated strongly with virus neutralization. Given the current focus on SARS-CoV-2 vaccination as the primary means of addressing the clinical sequelae of the current pandemic, it is concerning that so little attention has been paid to vaccine-induced mucosal immunity. This may help explain, at least in part, the observations reported on April 20, 2021, CDC update on vaccine efficacy, which showed little protection against infection, although disease severity was significantly moderated in infected vaccinated individuals. smith et al. reported that systemic and mucosal immunity after SARS-CoV-2 infection is an important dichotomy between systemic and mucosal immunity with important implications for treatment and pathological interpretation. recent independent studies by Lopez et al. and Cheemarla et al. have shown that the supply of antiviral interferon enables nasopharyngeal mucosal epithelial cells to inhibit the growth of SARS-CoV-2 and that interferon-induced mucosal genes thus serve as biomarkers of infection (see above and below in the section on innate immunity).
Another study measured the humoral response to SARS-CoV-2 and included the analysis of specific neutralizing antibodies present in serum, saliva, and bronchoalveolar fluid of 159 patients naturally infected with SARS-CoV-2. Again, early virus-specific humoral responses were dominated by IgA antibodies, peaking in the third week after infection, with IgA contributing more to virus neutralization than IgG or IgM antibodies. Although antiviral IgA serum concentrations decreased after 1 month, IgA remained detectable in saliva for up to 10 weeks. the same conclusion was independently reached by Butler et al. who recognized that serum neutralization and effector function were associated with the amount of systemic SARS-CoV-2-specific IgG response, whereas mucosal neutralization was associated with nasal SARS-CoV-2- IgA and less severe disease. A recent study examined the nature of mucosal immunity induced by two independent US mRNA vaccines (Pfizer/BioNTech's BNT162b2 and Moderna's mRNA-1273). Both vaccines induced antibodies to SARS-CoV-2 s protein, including neutralizing antibodies (nAbs) to RBD, with a significant increase in titers observed after the second vaccination. Similarly, s-protein and RBD antibodies were reported in saliva samples from healthcare workers vaccinated with mRNA, with 100% of subjects vaccinated with both vaccines showing IgG in saliva and 50% showing IgA in saliva.
Limited studies have been reported on vaccine-induced mucosal immunity in animals. A chimpanzee adenovirus vector vaccine encoding a pre-fused stable spike-in protein (ChAd-SARS-CoV-2-S) was studied, which was administered intramuscularly in mice expressing the human angiotensin-converting enzyme 2 receptors to prevent SARS-CoV-2 infection. A single dose induced systemic humoral and cell-mediated immune responses and protected mice from pulmonary infection, inflammation, and pathology without inducing sterile immunity, as confirmed by viral RNA assays following SARS-CoV-2 infection. In contrast, a single intranasal dose of the same vaccine induced high levels of neutralizing antibodies enhanced systemic and mucosal IgA and T cell responses, and prevented SARS-CoV-2 infection in the upper and lower respiratory tract. In a study in macaques, animals that received both vaccine inotropic initiation and boosting were compared with animals that received vaccine inotropic initiation but intranasal boosting. The vaccine used was the SARS-CoV-2 S protein adjuvant vaccine. Vaccination only induced bound and neutralizing antibodies with a persistent cellular immune system and mucosa, whereas the use of an intranasal boosting strategy resulted in weaker T cell and IgG responses but higher dimeric IgA and IFNα. no subgenomic RNA was detected in the upper or lower respiratory tract of either group of animals after the SARS-CoV-2 challenge compared to the original controls, again supporting the effectiveness of the mucosal immunization strategy.
Studies in children have further revealed the importance of mucosal immunity (and its induction) and ineffective immunity to SARS-CoV-2 infection. Unlike disease manifestations of other respiratory viruses that tend to be more severe in children, SARS-CoV-2 infection in children usually follows a more benign course. Pierce et al. found that SARS-CoV-2 copy number, ACE 2, and TMPRSS2 gene expression were similar in children and adults, but that infected children had increased expression of innate immune pathway-stimulating molecules (IFN signaling, the NLRP3 inflammatory vesicles and expression of other innate pathway-related genes). IFN-α2, IFN-γ, IP-10, IL-8, and IL-1β protein levels were higher in children's nasal fluids compared with adults, and SARS-CoV-2-specific IgA and IgG levels were similar in both groups. The course of disease following infection was much more benign in all children than in the adult cohort. Given the importance of secretory dimeric IgA (sIgA) in protecting mucosal surfaces from pathogens and the evidence (see above) implying the importance of mucosal sIgA in immunity to SARS-CoV-2, further interest was raised by a report by Quinti et al. showing a (genetic) lack of SARS-CoV-2-specific IgA and secretory IgA [49] in subjects with increased susceptibility and more violent disease progression. As they pointed out, unlike other primary antibody deficiencies, selective IgA deficiency is usually a "silent" unrecognized disease but may be an (unexplored) important cause of variation in response to SARS-CoV-2 infection. Colleen and colleagues also demonstrated an increased susceptibility to SARS-CoV-2 in patients with IgA deficiency.
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3. T Cell Immunity to SARS-CoV-2
It has been known for some time that activated T lymphocytes are critical for protective immunity against viral infections. This is in line with what we know about the completely different antigen recognition by B cells and T cells. The latter recognize cell surface MHC-presenting epitopes that are altered upon viral infection and can therefore destroy potential "virus factories" before live virus replication is complete within infected cells. Although monitoring (serum) Ig makes it easier to assess the development of the immune response to a pathogen, as mentioned above, it may provide little information on the development of protective immunity in the infected host. This issue is discussed in further detail in a recent review. The correlation between antibody response and disease is low, especially in mild infections, and stronger responses usually reflect more severe clinical disease. In contrast, viral-reactive T cell immunity lasts longer and natural infection with SARS-CoV-2 induces extensive epitope coverage by CD4 and CD8 T cells. S-protein immunity is less restricted compared to Ig responses, but the relevance to disease outcome remains to be determined. The correlation of clinical outcomes with laboratory markers of cell-mediated immunity, not only with antibody responses, may further shed light on how to optimize the induction of protective immunity after natural infection and vaccination. A preliminary report of such investigations was recently published in subjects aged 18-55 years up to 8 weeks after a single dose of the ChAdOx1 nCoV-19 vaccine. CD4 T-cell responses were characterized by interferon-γ and tumor necrosis factor-α cytokine secretion, with IgG1 and IgG3 antibodies predominating. Some CD8+ T cells have also been induced to monofunctional, multifunctional, and cytotoxic phenotypes, with little clinical significance documented to date. A more detailed study on CD8 T cell immunity after the natural infection has also been recently reported. Targeting structural and non-structural targets in the SARS-CoV-2 proteome, highly heterogeneous responses were found in numerous CD8+ epitopes and multiple (6)HLAs, with up to 52 unique epitopes documented, although any relevance to the results remains to be confirmed.
Zhuang and his colleagues studied animals in an attempt to gain a deeper understanding of T-cell resistance mechanisms. Their data suggest that the type I interferon pathway is critical for generating an optimal antiviral T-cell response after SARS-CoV-2 infection in mice and that T-cell vaccination may even partially protect infected animals from severe disease.
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Reginald M. Gorczynski 1, Robyn A. Lindley 2,3, Edward J. Steele 4,5and Nalin Chandra Wickramasinghe 6,7,8
1. Institute of Medical Science, Department of Immunology and Surgery, University of Toronto, Toronto, ON M5S 3G3, Canada
