Part 2 Nature Of Acquired Immune Responses, Epitope Specificity And Resultant Protection From SARS-CoV-2

How Does the Clinical Efficacy of SARS-CoV-2 Vaccines Align with the Induction of Immunity?

1. Innate Immunity

The potential role of innate immunity in SARS-CoV-2 infection was mentioned in the introduction but is largely unexplored. Innate immunity is triggered by a family of so-called pattern recognition receptors known to induce interferons and a variety of cytokines that activate cells of the myeloid and lymphocyte differentiation pathways to defend against pathogens. Live attenuated vaccines for tuberculosis, measles, and polio have all been shown to "train" the innate immune system through histone modification and epigenetic reprogramming of monocytes to enhance broad resistance to other infectious diseases, as may be the case with SARSCoV-2 infection.

A recent study comparing innate immune responses to influenza and SARS-CoV-2 in nasal washes from infected adults showed important differences in innate immunity following SARS-CoV-2 infection, with reduced IFN-related transcripts in neutrophils, macrophages, and epithelial cells and reduced epithelial cell-cell interactions compared to influenza-infected individuals.GWAS studies also imply an important link between the IFN pathway and disease severity. In an important new publication, Inanova et al. compared various immune parameters (SARS-CoV-2 BNT162b2 mRNA) in subjects after natural infection or SARS-CoV-2 vaccination. Both infection and vaccination-induced innate and adaptive immune responses, but only in SARS-CoV-2 infected patients and in unvaccinated individuals, characterized by an enhanced interferon response. This in turn correlates with the upregulation of cytotoxic genes in peripheral T cells and innate-like lymphocytes in the same cohort. Furthermore, as assessed by B and T cell receptor libraries, most clonal B and T cells were effector cells in SARS-CoV-2 infected patients, whereas in vaccinated subjects, the expanded cells were predominantly circulating memory cells. Further complicating immune protection after intentional vaccination is data we have summarized elsewhere, which suggests that natural herd immunity has developed on a population scale across Europe before the vaccine rollout actually begins. A recently published article suggests another promising approach to boost broad-spectrum intranasal antiviral innate immunity in the upper respiratory tract using local delivery of an engineered defective viral genome, ultimately leading to enhanced local and distal type I interferon responses.

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2. B Cell Immunity following Vaccination

Studies of naturally infected populations recovering from mild SARS-CoV-2 infection have shown that SARS-CoV-2-specific IgG, neutralizing antibodies, and memory B and memory T cells persist for more than several months. Memory T cells secreted cytokines and expanded upon antigen reencounter, and memory B cells expressed receptors capable of neutralizing the virus upon monoclonal antibody expression. Similarly, Dan et al. reported memory cell survival of B and T cells for more than 8 months after infection, although the clinical significance of this has not been addressed as B cell memory responses appear to be more durable than T cell immunity. This observation of long-term persistent IgG neutralization after natural infection is consistent with a German cohort study and other studies showing that persistent virus-neutralizing antibodies correlate with the outcome and that even viral rebound after early clearance is associated with lower RDD-specific IgA and IgG antibody induction and low levels.

How does the development of protective Ig responses after natural infection and vaccination compare? In particular, given the (relatively rapid) antigenic drift of SARS-CoV-2 reported in the last 8 months, how does this affect vaccine-induced immunity to infection? In particular, mutations in the S protein could theoretically affect binding to one (or both) of the cellular receptors ACEII or antibody binding. Shared mutations that increase binding to ACEII and are heritable in variants B.1.1.7, (UK) P.1, (Brazil); B.1.351 (South Africa). variants B.1.351 and P.1 also show another mutation that reduces the binding of neutralizing antibodies, causing (partial) immune escape and favoring reinfection. The contribution of the context of immune enhancement (in "high-risk" populations) to the emergence of new mutations remains to be explored. A recent analysis of publicly available genomic sequence and epidemiological data during the second outbreak in Victoria, Australia, discussed the possibility of rapid SARS-CoV-2 amplification in the context of a failed innate immune response (e.g., in elderly co-morbidities). Thus, these publicly available data have shown that putative further deaminase-mediated mutations in the APOBEC and ADAR -deaminase motifs (C-sites, a -sites) in the SARS-CoV-2 genome isolated from such patients favor casual expansion of the common genomic sequence.

Analysis of antibody and memory B cell responses to two anti-SARS-CoV-2 mRNA vaccines in 20 volunteers showed similar plasma-neutralizing activity and relative numbers of rbd-specific memory B cells in the vaccinated and naturally infected cohorts. However, activity against the SARS-CoV-2 variant was significantly reduced [69]. Collier et al. reported a similar, albeit small, reduction in neutralizing activity and binding to the RBD motif against B.1.1.7 SARS-CoV-2 after vaccination with an mRNA-based vaccine. The loss of neutralizing activity was even greater after the introduction of a second variant in the B.1.1.7 background, which they hypothesized could pose a threat to the efficacy of this vaccine. Reports from other groups have raised similar concerns.ACEII binding and neutralizing Ab were isolated after natural infection with many different variants of SARS-CoV-2, also highlighting the conservation of RBD binding to some of the more conserved loci.

A more comprehensive summary reportedly used 506768 SARS-CoV-2 genomic isolates, including S-RBD mutations from patients, to explore the effects of immunization against an increasing number of SARS-CoV-2 variants, and also concluded that most variants are associated with increased ACEII binding and therefore may be more infectious. Many new RBD mutants were identified that may affect the neutralization of Ig binding to the RBD, including those now described in California variant B.1.427 and Mexico variant B.1.1.222, the latter significantly enhancing the infectivity of the latter. The authors concluded that "genetic evolution of SARS-CoV-2 on the RBD may be regulated by host gene editing, viral proofreading, random genetic drift, and natural selection, and (could) generate additional infectious variants, which could compromise existing vaccine and antibody therapies." Similar concerns have been raised by Venkatakrishnan et al. However, despite this pessimistic prediction, there is clear evidence that vaccines currently in use produce clinically significant protective responses to infection in high-risk populations, as highlighted by a recent report exploring hospitalization after vaccination.

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3. T Cell Immunity following Vaccination

As previously mentioned, it seems self-evident that systematic analysis of T-cell epitopes identified by subjects after natural infection, in relation to disease outcome, is essential to guide the interpretation of monitored patient responses and the development of protective vaccines that may prove effective. A US government-led clinical trial was designed in 2020 with this in mind (currently in the data analysis phase, but not yet reported). Blood samples from SARS-CoV-2-infected patients who have recovered from infection were screened using genome-wide, high-throughput screening techniques in the hope of identifying T-cell receptors and immunogenic viral epitopes on SARS-CoV-2, which may contribute to the development of durable protection against SARS-CoV-2. Preliminary reports from other research groups using more rigorous study designs have raised the hope that these studies will have some utility. Thus, longitudinal analysis (up to 6 months post-infection) showed a decrease in S and nucleocapsid-specific antibody responses, while, in contrast, functional T-cell responses remained sustained or even increased over the same period and many dominant T-cell epitopes were identified [81]. A recent genome-wide screening approach was used to explore CD8 immunity in recovering SARS-CoV-2 individuals. More than 120 immunogenic peptides were identified from a library of approximately 3140 MHC class I binding peptides covering the entire SARS-CoV-2 genome, a subset of which was found to represent immunodominant SARS-CoV-2 T-cell epitopes. Pre-existing T-cell recognition features were observed in naive individuals, possibly reflecting prior exposure to coronavirus infection. More importantly, a robust T cell activation profile can be demonstrated in previously infected patients, which is most pronounced in severely ill patients, while minimal responses are shown in mildly ill or naive (uninfected) individuals.

Further studies sought to explore the nature of recognition of viral variants in vaccinated/infected versus naive subjects in order to compare the data with that observed in similar groups comparing Ig responses. Researchers characterized subjects receiving either Pfpfizer - Biontech (BNT162b2) or Moderna (mRNA-1273) mRNA-based SARS-CoV-2 vaccine and found that they exhibited a broad T-cell response to SARS-CoV-2- s protein, with only 4/23 targeting peptides likely to be affected by UK (B.1.1.7) and South African (B.1.351) variants. In contrast to the antibody data discussed above, CD4+ T cells from vaccine recipients recognized both variants of the stinger protein as effectively as they recognized the s protein from the ancestral virus. Interestingly, a 3-fold increase in CD4+ T cell responses to influenza s-peptides after vaccination implies cross-protection (after SARS-CoV-2 vaccination) against some endemic coronaviruses [83]. Others have reported that SARS-CoV-2-specific T cells from vaccinated individuals recognize mutated SARS-CoV-2 isolates and that vaccinated recovering patients have more persistent nasopharyngeal directed SARS-CoV-2-specific T cells compared to infection-naïve. However, mention should be made of a conflicting report by Gallagher et al. that used standard functional assays to assess t-cell immunity to SARS-CoV-2 in uninfected, recovered, and vaccinated individuals. While vaccinated individuals exhibited stronger t-cell responses to wild-type spike-in and nucleocapsid proteins compared to recovered patients, a rather low t-cell response to spike-in variants (B.1.1.7, B.1.351 and B.1.1.248) was observed in vaccinated but otherwise healthy donors, similar to the Ig data discussed earlier. Apart from differences in the assays used, again acknowledging no correlation with clinical utility, there is no obvious explanation for the differences between the studies reported in the literature.

The importance of understanding T-cell immunity to SARS-CoV-2 is confirmed by a recent report investigating the use of in vitro amplified SARS-CoV-2 immune T cells in immune-compromised subjects for follow-up of peripatetic immunotherapy. The group amplified SARS- CoV-2-specific T cells from recovering donors using a GMP device and a combination of membrane, spike-in, and nucleocapsid peptides. IFN-γ was produced in 27 (59%), 12 (26%), and 10 (22%) of the recovering donors and 2 of the 15 unexposed controls, respectively. multifunctional cd4-restricted t-cell epitopes were identified within conserved regions of membrane proteins that induce multifunctional t-cell responses. The authors suggest that this may contribute to the development of effective vaccines and t-cell therapies for patients with immunocompromised blood disorders or after bone marrow transplantation. A thorough review of current vaccine candidates in phase 3 trials was recently published.

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Unexpected Adverse Effects of SARS-CoV-2 Vaccination

It seems appropriate to conclude the current discussion with some reflections on the adverse effects noted with SARS-CoV-2 vaccination. mRNA vaccines, a new formulation of synthetic mRNA strands encoding the SARS-CoV-2-S glycoprotein packaged in lipid nanoparticles that deliver mRNA to cells, were heralded for rapid and novel introduction into the clinic by Verbeke et al. Verbeke et al. believe that we are at the beginning of a "new dawn" in vaccinology. However, as they acknowledge, there are still huge gaps in our understanding. Data from two widely used mRNA vaccines, BNT162b2 and mRNA-1273, suggest that nucleoside-modified mRNA approaches can provide higher maximum tolerated doses, and thus may go some way to explaining why these approaches, rather than the adenovirus-encoded s-protein in more traditional vaccines, can produce a faster antibody response. It is unclear why two similar (nucleoside-modified) mRNA vaccines trigger very different s-specific CD8+ T cell responses. There are many plausible hypotheses, including but not limited to, that there may be differences in innate responses to the two candidates; that mRNA sequence design (e.g., UTR encapsulation, codon optimization) may contribute to vaccine efficacy and reactogenicity (minor adverse reactions). Undoubtedly, a deeper understanding of the in vivo delivery efficiency and specific innate immune effects of different mRNA vaccines will help to design safer and more effective mRNA vaccines in the future.

Others have focused their attention on the adverse effects of the SARSCoV-2 vaccine already in use. First, these include vaccine-induced immune thrombotic thrombocytopenia (VITT) following vaccination with the adenoviral vector SARS-CoV-2 vaccine ChAdOx1 nCoV-19. Very few patients (less than 1 in 100,000) develop thrombosis and thrombocytopenia 5-24 days after vaccination, usually at unusual sites (cerebral venous sinus; tests strongly positive in PF4/polyamide immunoassays (EIAs) and shows serum-induced platelet activation, which is maximal in the presence of PF4. It is unclear which components of the vaccine are responsible for enhancing the response to the unrelated host protein (PF4) and why this response occurs only after exposure to adenoviral vectors. pF4 may be a bystander component of the immune complex that activates platelets. Thiele et al. evaluated the frequency of anti-PF4/polyanion antibodies in healthy vaccines and assessed the frequency of anti-PF4 antibodies in vaccinated ChAdOx1 nCoV-19 or BNT162b2 (BioNTech/Pfizer) vaccines whether PF4/polyanion EIA-positive sera exhibited platelet activation properties. Although 19 of 281 participants tested positive for anti-pf4/polyanion antibodies after vaccination (all 6.8% [95% CI, 4.4-10.3]; BNT162b2: 5.6% [95% CI, 2.9-10.7]; ChAdOx1 nCoV-19: 8.0% [95% CI, 4.5-13.7%]), the None of the PF4/polyanionic EIA-positive samples induced platelet activation in the presence of PF4. They concluded that positive PF4/polyanionic EIAs may occur after SARS-CoV-2 vaccination with mRNA- and adenovirus-based vectors, but that most of these antibodies may have minor clinical relevance (if any). Pathogenic platelet-activating antibodies that cause VITT are uncommon after vaccination.

Other research groups are concerned about the theoretical risks associated with current vaccines, arguing that their "rush to use" has overlooked potential problems with their use, particularly concerns about the induction of autoimmune responses. For example, the failure of the SARS vaccine in animal trials involved pathogenesis consistent with immune initiation, possibly involving autoimmunity in lung tissue due to prior exposure to SARS spike-in proteins. comparison of immunogenic epitopes of SARS-CoV-2- s proteins, and homology matches of other SARS-CoV-2 proteins to human proteins. The authors concluded that only one immunogenic epitope in SARS-CoV-2 has no homology with human proteins and that the overlap of many of these with human proteins could theoretically help explain some of the symptoms associated with SARS-CoV-2 pathogenesis. In a similar vein, Lu et al. asked whether the rapid introduction of the current SARS-CoV-2 vaccine to the market would put us at risk of causing previously recognized neurological disorders, including vaccine-related demyelinating diseases, fever-induced seizures, and other defects. Other studies have focused on myocarditis following SARS-CoV-2 infection and/or vaccination, as well as other more subtle autoimmune types of reactions following SARS-CoV-2 infection [98]. It is self-evident that only time will tell how serious a problem this is compared to past experience.

Concluding Remarks

Finally, we recall that pandemics of the type we have experienced in the past 18 months are far from a new phenomenon. Similar epidemics have occurred repeatedly throughout thousands of years of human history, often leading to severe population declines and, in some cases, even the collapse of empires. In the past, however, the social role of responding to such epidemics has been limited - limited primarily to alleviating the suffering caused by the disease and perhaps isolating the infected victims as much as possible. At this stage, it is clear that no globally coordinated response is possible, nor is any large-scale intervention to minimize transmission and thus hasten the end of a pandemic. The advantage we have now is the type of scientific knowledge we have discussed in this paper. If people use this knowledge honestly and dispassionately, a new utopia beckons; otherwise, we may be no better off now than we were in previous times, and in some people's minds even worse off.

All pandemics are, of course, self-limiting and eventually end by creating herd immunity to the infectious agent. The global response to the current pandemic, including draconian and often punitive restrictions on individual freedom, is clearly unprecedented in history. The rationale for such draconian measures is based on the claim that scientific advances provide a shortcut to the natural immunization process that will greatly reduce the total number of infections and deaths. We show in this review that some aspects of the scientific arguments currently being deployed are either flawed or seriously flawed.

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Summary

We are hopefully approaching a defensive phase in our response to the SARS-CoV-2 pandemic, with more widespread vaccination, protection of vulnerable populations (especially the elderly), and adherence to better public health measures that continue to improve the overall outlook. Significant mismanagement and misunderstandings at all levels - political, social, ethical, scientific, and medical - combined with serious errors of judgment, have clearly resulted in the loss of life. As mentioned above, it can be argued that we still do not recognize the importance of implementing basic scientific knowledge, both in terms of new research and understanding old observations, which may improve the future course of this disease even now. In the face of having implemented so many previously untried and untested treatments, we need to remain vigilant as new signs and symptoms emerge in treated patients, an early indication of adverse events for which VITT may be just the tip of the iceberg. The philosopher George Santayana once said, "Those who cannot remember the past are doomed to repeat it." We need to make sure that the valuable lessons learned at all levels over the past 18 months are not forgotten.

Cistanche can improve Immunity

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Research has shown that Cistanche contains bioactive compounds that have immunomodulatory effects. These compounds can help regulate the immune response by increasing or decreasing immune cell activity as needed. Cistanche has also been found to increase the production of cytokines, which are proteins that help regulate immunity.

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While these studies suggest that Cistanche may have potential benefits for boosting the immune system, more research is needed to confirm these findings and determine the optimal dosages and duration of treatment. In addition, it is important to note that Cistanche should not be used as a substitute for medical treatment or advice.

In conclusion, Cistanche may have potential immune-boosting effects due to its immunomodulatory properties. However, further research is needed to confirm these findings and determine their optimal use in promoting immune health.

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1 Institute of Medical Science, Department of Immunology and Surgery, University of Toronto, Toronto, ON M5S 3G3, Canada

2 Department of Clinical Pathology, Faculty of Medicine, Dentistry & Health Sciences, University of Melbourne, Melbourne, VIC 3000, Australia; robyn.lindley@unimelb.edu.au

3 GMDx Group Ltd., Melbourne, VIC 3000, Australia

4 C.Y.O’Connor ERADE Village Foundation, Piara Waters, Perth, WA 6207, Australia; e.j.steele@bigpond.com

5 Melville Analytics Pty Ltd., Melbourne, VIC 3000, Australia

6 Buckingham Centre for Astrobiology, University of Buckingham, Buckingham MK18 1EG, UK; NCWick@gmail.com

7 Centre for Astrobiology, University of Ruhuna, Matara 81000, Sri Lanka

8 National Institute of Fundamental Studies, Kandy 20000, Sri Lanka * Correspondence: reg.gorczynski@utoronto.ca