20200506W Day 127: Immunology of COVID-19

2020_Immunology_of_COVID19
Figure 6: Mechanism of Action for Potential Drug Therapies (reference: https://doi.org/10.1016/j.immuni.2020.05.002)

Today, the randomness of the universe brought an interesting research paper into my sights, Immunology of COVID-19: current state of the science, and so I thought I’d read through it and take notes for the future. It is a critical review of both preprint and peer-reviewed articles by trainees and faculty members of the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai (PrIISM).

I’ll quote part of the abstract so that you know what you are getting into if you continue reading:

In this review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS- CoV-2 infection.

I’ll be taking various quotes of interest from the paper and giving my thoughts along the way.

China reported this outbreak to the WHO on December 31st, 2019 and soon after identified the causative pathogen as a betacoronavirus with high sequence homology to bat coronaviruses using angiotensin-converting enzyme 2 (ACE2) receptor as the dominant mechanism of cell entry.

The following day, I felt a universe shift and decided to begin blogging about it using this blog which I have used on a very irregular basis. In 2020 Day 9: New Strain of Coronavirus found in Wuhan, China, I was drawn into this story to the point that I researched coronaviruses and wrote the following:

Four identified coronaviruses (HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1) are endemic in humans and cause up to 30% of respiratory tract infections worldwide each year. HCoV-NL63 has been associated with acute laryngotracheitis (croup). Coronoviruses have different tolerances to genetic variability with some (i.e. HCoV-229E) having little genetic variability worldwide and primarily isolated in humans and others (i.e. HCoV-OC43) showing high genetic variability across time and location. Most cases of coronavirus infection are self-limiting and will naturally run its course.

and perhaps because I had also been sick for two weeks, had purchased some Chinese herbs at an Acupuncturist, and had been dissolving zinc under my tongue with OJ as my grandmother had taught me.

Back to the review paper, which begins by discussing our first line of defense against viruses – innate immune sensing. Since SARS-CoV-2 is an RNA virus, the standard innate immune sensing pathways for RNA viruses are identified. Rather than quote from the paper, I’ll list the “characters” involved to familiarize myself with the acronyms:

  1. Pattern Recognition Receptor (PRR) – upon activation, PRRs trigger the secretion of cytokines via a downstream signaling cascade
  2. Retinoic Acid-Inducible Gene I (RIG-I) – a cytosolic PRR that recognizes short viral double-stranded RNA (dsRNA) and other irregular RNAs
  3. RIG-I Like Receptor (RLR) – a type of cytosolic PRR that detect a broad range of viral RNA and activate the Inflammosome.
  4. Toll-Like Receptor (TLR) – a type of PRR, a single-pass membrane-spanning protein often found on sentinel cells (e.g. macrophages, dendritic cells) that recognize PAMPs (e.g. di/triacylated lipopeptides, LPS, Profilin, Flagellin, CpG DNA, ssRNA, dsRNA, 23s rRNA)
  5. Pathogen-Associated Molecular Pattern (PAMP) – a conserved microbial structure of a pathogen
  6. Cytokines
  7. Interferon I (IFN-I)
  8. Interferon III (IFN-III)
  9. Proinflammatory tumor necrosis factor alpha (TNF-α)
  10. Interleukin-1 (IL-1)
  11. Interleukin-6 (IL-6)
  12. Interleukin-18 (IL-18)
  13. Lymphocyte antigen 6 complex locus E (LY6E) – shown to interfere with SARS-CoV-2 spike (S) protein-mediated membrane fusion
  14. Melanoma Differentiation-Associated protein 5 (MDA5) – a RIG-I-like receptor

The paper then continues with techniques that coronaviruses have evolved in order to evade out innate immune system. Studies have found that:

  1. SARS-CoV-1 suppresses IFN release in vitro and in vivo;
  2. Patients with severe COVID-19 have “remarkably impaired IFN-I signatures as compared to mild or moderate cases”;
  3. Coronaviruses encode an endoribonuclease, NSP15, that cleaves 5′ polyuridine byproducts of viral replication, thereby avoiding detection by MDA5;
  4. SARS-CoV-1 N-protein inhibits TRIM25 activation of RIG-I;
  5. MERS-CoV proteins NS4a and NS4b also inhibit RLRs;
  6. SARS-CoV-1 ORF9b suppresses MAVS signaling and SARS-CoV-2 ORF9b interacts, via Tom70, with the signaling adaptor MAVS;
  7. SARS-CoV-1 M protein and MERS-CoV ORF4b inhibit the TBK1 signaling complex and SARS-CoV-2 NSP13 interacts with TBK1 and SARS-CoV-2 NSP14 interacts with an activator of TBK1;
  8. SARS-CoV-1 proteins PLP, N, ORF3b and ORF6 block IRF3 phosphorylation and nuclear translocation;
  9. SARS-CoV-1 PLP and MERS-CoV ORF4b and ORF5 inhibit NF-kB;
  10. SARS-CoV-1 and MERS-CoV NSP1 generally inhibit host transcription and translation;
  11. SARS-CoV-1 ORF6 antagonizes STAT1 nuclear translocation;
  12. SARS-CoV-2 ORF6 shares only 69% sequence homology with SARS-CoV-1 and appears to not antagonize STAT1 nuclear translocation since COVID-19 fails to limit STAT1 phosphorylation as happens with SARS-1;
  13. “Animal models of SARS-CoV-1 and MERS-CoV infection indicate that failure to elicit an early IFN-I response correlates with the severity of disease. Perhaps more importantly, these models demonstrate that timing is key, as IFN is protective early in disease but later becomes pathologic. Perhaps, interferon-induced upregulation of ACE2 in airway epithelia may contribute to this effect. Furthermore, while pathogenic CoVs block IFN signaling, they may actively promote other inflammatory pathways contributing to pathology.”
  14. “SARS-CoV-1 ORF3a, ORF8b, and E proteins enhance inflammasome activation, leading to secretion of IL-1β and IL-18, which are likely to contribute to pathological inflammation. Similarly, SARS-CoV-2 NSP9 and NSP10 might induce IL-6 and IL-8 production, potentially by inhibition of NKRF, an endogenous NF-kB repressor. Collectively, these pro-inflammatory processes likely contribute to the ‘cytokine storm’ observed in COVID-19 patients and substantiate a role for targeted immunosuppressive treatment regimens.”

The paper discusses the roll in COVID-19 of myeloid cells, innate lymphoid cells, and T cells. It then discusses the B Cell response:

The humoral immune response is critical for the clearance of cytopathic viruses and is a major part of the memory response that prevents reinfection. SARS-CoV-2 elicits a robust B cell response, as evidenced by the rapid and near-universal detection of virus- specific IgM, IgG and IgA, and neutralizing IgG antibodies (nAbs) in the days following infection. The kinetics of the antibody response to SARS-Cov-2 are now reasonably well described (Huang et al., 2020a).

Similar to SARS-CoV-1 infection, seroconversion occurs in most COVID-19 patients between 7 and 14 days after the onset of symptoms, and antibody titers persist in the weeks following virus clearance.

Antibodies binding the SARS-CoV-2 internal N protein and the external S glycoprotein are commonly detected.

The receptor binding domain (RBD) of the S protein is highly immunogenic and antibodies binding this domain can be potently neutralizing, blocking virus interactions with the host entry receptor, ACE2.

Anti-RBD nAbs are detected in most tested patients.

Although cross-reactivity to SARS-CoV-1 S and N proteins and to MERS- CoV S protein was detected in plasma from COVID-19 patients, no cross-reactivity was found to the RBD from SARS-CoV-1 or MERS-CoV. In addition, plasma from COVID-19 patients did not neutralize SARS-CoV-1 or MERS-CoV

Regarding long-term protection of antibodies, which would also likely be true of a vaccine that induced antibodies:

Studies of common coronaviruses, SARS-CoV-1 and MERS-CoV indicate that virus specific antibody responses wane over time, and, in the case of common coronaviruses, result in only partial protection from reinfection. These data suggest that immunity to SARS-CoV-2 may diminish following a primary infection and further studies will be required to determine the degree of long-term protection.

But maybe having antibodies is not necessarily a good thing:

Several studies have demonstrated that high virus-specific antibody titers to SARS- CoV-2 are correlated with greater neutralization of virus in vitro and are inversely correlated with viral load in patients (Figure 4) (Okba et al., 2020; Wölfel et al., 2020; Zhao et al., 2020a). Despite these indications of a successful neutralizing response in the majority of individuals, higher titers are also associated with more severe clinical cases (Li et al., 2020b; Okba et al., 2020; Zhao et al., 2020a; Zhou et al., 2020a), suggesting that a robust antibody response alone is insufficient to avoid severe disease.

This was also observed in the previous SARS-CoV-1 epidemic, where neutralizing titers were found to be significantly higher in deceased patients compared to patients who had recovered (Zhang et al., 2006). This has led to concerns that antibody responses to these viruses may contribute to pulmonary pathology, via antibody-dependent enhancement (ADE) (Figure 4).

The authors specifically mention vaccine development:

Vaccine trials will need to consider the possibility of antibody-driven pathology upon antigen re-challenge; strategies using F(ab) fragments or engineered Fc monoclonal antibodies may prove particularly beneficial in this setting (Amanat and Krammer, 2020).

They then continue with a discussion of predictors of COVID-19 disease risk and severity. Some associations that have been found:

  1. Blood group A is associated with a higher risk of acquiring COVID-19 than non-A blood groups. Blood group O is associated with a lower risk of acquiring COVID-19 than non-O blood groups. Similar results were found for SARS-1.
  2. The most consistent findings across the different studies were elevated levels of CRP, LDH and D-dimer, as well as decreased blood platelet and lymphocyte counts (Yan et al., 2020b; Zhou et al., 2020d).”
  3. elevated IL-6 levels were detected in hospitalized patients, especially critically ill patients, in several studies, and are associated with ICU admission, respiratory failure, and poor prognosis (Chen et al., 2020f; Huang et al., 2020b; Liu et al., 2020f)”
  4. Total T cell, helper T cell, and suppressor T cell counts were significantly lower, and the TH/TS ratio was significantly higher in patients who died from infection, as compared to patients who were discharged.”
  5. direct correlation with patient viral load will be important to provide a greater understanding of underlying causes of morbidity and mortality in COVID-19 and the contribution of viral infectivity, hyper-inflammation and host tolerance (Medzhitov et al., 2012).”
  6. lymphopenia, increases in proinflammatory markers and cytokines and potential blood hypercoagulability characterize severe COVID-19 cases with features reminiscent of cytokine release syndromes. This correlates with a diverse clinical spectrum ranging from asymptomatic to severe and critical cases. During the incubation period and early phase of the disease, leukocyte and lymphocyte counts are normal or slightly reduced. After SARS-CoV-2 binds to ACE2 overexpressing organs, such as the gastrointestinal tracts and kidneys, increases in non-specific inflammation markers are observed. In more severe cases, a marked systemic release of inflammatory mediators and cytokines occurs, with corresponding worsening of lymphopenia and potential atrophy of lymphoid organs, impairing lymphocyte turnover (Terpos et al., 2020).

Next, the authors discuss small molecules that inhibit one or more stages of the virus life cycle.  Antivirals for SARS-CoV-1, MERS-CoV, and other viruses have been tested against SARS-CoV-2. These fall into three categories: broad spectrum, protease inhibitors, and RdRp inhibitors.

Broad spectrum antivirals that work against other RNA viruses have been evaluated with SARS-CoV-2. Quoting the paper:

A number of small molecules with known antiviral activity against other human RNA viruses are being evaluated for efficacy in treating SARS-CoV-2. The ribonucleoside analog β-D-N4-hydroxycytidine (NHC) reduced viral titers and lung injury in mice infected with SARS-CoV-2 via introduction of mutations in viral RNA (Sheahan et al., 2017). Further, an inhibitor of host DHODH, a rate-limiting enzyme in pyrimidine synthesis, was able to inhibit SARS-CoV-2 growth in vitro with greater efficacy than remdesivir or chloroquine (Wang et al., 2020e; Xiong et al., 2020). Merimepodib, a non-competitive inhibitor of the enzyme Inosine-5′-monophosphate dehydrogenase (IMPDH), involved in host guanosine biosynthesis, is able to suppress SARS-CoV-2 replication in vitro (Bukreyeva et al., 2020). Finally, N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC), which was previously shown to efficiently reduce infection by the less pathogenic human coronavirus HCoV-NL63, was also found to inhibit MERS-CoV and pseudotyped SARS-CoV-2 in human airway epithelial cells (Milewska et al., 2020).

Of nine existing HIV protease inhibitors (nelfinavir, lopinavir, ritonavir, saquinavir, atazanavir, tipranavir, amprenavir, darunavir, and indinavir), the most potent inhibitor in SARS-CoV-2 infected Vero cells was found to be nelfinavir.

RdRP is the coronavirus RNA-dependent RNA polymerase. It catalyzes the synthesis of viral RNA. As an adenosine triphosphate analog, Remdesivir binds to RNA strands and prevents additional nucleotides from being added, causing the termination of viral RNA transcription. Remdesivir has already been shown to be effective against SARS-1 and MERS in animal models. A study on 12 rhesus macaques infected with SARS-CoV-2 showed “a reduction in lung viral loads and pneumonia symptoms, but no reduction in virus shedding”. It also provided “evidence that if administered early enough, Remdesivir may be effective at treating SARS-CoV-2 infections.”

Antiviral clinal trials were discussed and a random control trial of Remdesivir is worth mentioning:

Preliminary results from a larger NIAID RCT with more than 1000 patients were announced with remdesevir to be associated with quicker time to recovery: 11 days compared with 15 days (Ledford, 2020). A non-significant benefit in mortality was also noted and the trial was stopped early to allow access to remdesivir in the placebo arm. Complete safety data and full publication are awaited but this study offers encouraging results and have resulted in an FDA Emergency Use Authorization for remdesivir in hospitalized COVID-19 patients.

One of the most controversial treatments, hydroxychloroquine, was discussed under the heading “Therapeutic Immunomodulation for COVID-19 Treatment”. To avoid missing or misinterpreting anything here, I am including the full quote from the paper on modes of action and immunological impact:

Chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) have gained traction as possible therapeutics for COVID-19. Both drugs are used as antimalarial agents and as immunomodulatory therapies for rheumatologic diseases. However, the application of CQ and HCQ to COVID-19 stems for their past use as antivirals (Savarino et al., 2003), including for SARS-CoV-1 (Keyaerts et al., 2004; Vincent et al., 2005). CQ and HCQ interfere with lysosomal activity and have been reported to have immuno-modulatory effects. CQ augments antigen processing for MHC class I and II presentation, directly inhibits endosomal TLR7 and TLR9, and enhances the activity of regulatory T cells (Garulli et al., 2008; Lo et al., 2015; Schrezenmeier and Dörner, 2020; Thomé et al., 2013a, 2013b). Early studies involving in vitro infection of host cells with SARS-CoV-2 demonstrated that both CQ and HCQ significantly impact endosomal maturation, resulting in increased sequestration of virion particles within endolysosomes. However, there has been conflicting evidence whether CQ is more potent than HCQ in reducing viral load (Liu et al., 2020d; Wang et al., 2020b; Yao et al., 2020a). Notably, one group reported that treatment of infected cells with HCQ before and during infection significantly reduced viral load, suggesting that combined prophylactic and therapeutic HCQ use yields maximum efficacy (Clementi et al., 2020). To better understand host immune responses to treatment, one group compared bulk transcriptomic changes in primary PBMCs treated with HCQ for 24 hours to PBMCs from confirmed SARS-CoV-2 positive patients and controls, followed by a comparison of HCQ treated primary macrophages to BAL and postmortem lung biopsies from COVID-19 patients (Corley et al., 2020). Across all comparisons, there was minimal overlap between host differential gene expression and genes altered by in vitro HCQ treatment. Thus, the potential mechanistic action of HCQ in the context of SARS-CoV-2 remains poorly defined.

and also on evaluation of HCQ efficacy in clinical trials:

Despite the apparent widespread use of HCQ and CQ to treat COVID-19 (Figure 6B), few controlled clinical trials have been performed so far and thus the potential benefits of these drugs for COVID-19 remains controversial. One of the earliest trials (2020- 000890-25) was a single-arm, open label trial of 600mg daily HCQ in 20 COVID-19 patients. They reported that HCQ alone, or in combination with the antibiotic azithromycin (AZ), reduced viral load by day 6 (Gautret et al., 2020a). A follow up trial in 80 patients treated with HCQ + AZ reported that 93% of patients had a negative PCR result on day 8 of treatment, and 81.3% were discharged within 10 days of treatment. However, it is important to note that both trials had no control arms (Gautret et al., 2020b). Rigorous statistical analyses by others that accounted for the patients excluded from the original analysis found limited evidence for HCQ monotherapy (Hulme et al., 2020; Lover, 2020). A double blind rRCT assessed HCQ monotherapy in the treatment of mild COVID-19 (ChiCTR2000029559) (Chen et al., 2020h). A total of 62 patients were enrolled; the treatment arm received 400 mg HCQ daily over 5 days. By day 6, patients who received HCQ had clinical resolution on average one day earlier than controls; no patients progressed to severe disease compared to 4 patients in the control arm. In a smaller RCT treated 30 patients with mild COVID-19 (NCT04261517) with 400 mg HCQ for 7 days, there were no significant differences in the number of patients with negative PCR results on day 7 (all but one positive), median duration of hospitalization, time to fever resolution, or progression of disease on chest CT (Chen et al., 2020c). The largest RCT to date enrolled 150 patients with mild COVID-19 across 16 centers in an open label trial of HCQ + standard of care (ChiCTR2000029868). There were no significant differences between groups in conversion to negative SARS-CoV-2 RT-PCR result on day 28 or rate of symptom resolution; there were significantly more adverse events in the HCQ arm, though largely non-serious; they reported some evidence for faster normalization of C-reactive protein in the patients who received HCQ plus standard of care, but this finding was not significant (Tang et al., 2020b). A meta- analysis including most of the studies described here found no clinical benefits to patients receiving standard of care plus an HCQ regimen (Shamshirian et al., 2020).

Two studies have assessed HCQ efficacy in severe COVID-19. In a prospective study of 11 patients who had received 600 mg HCQ over 10 days with AZ on days 1-5, there were several patients with worsening clinical status and one death; 8/10 patients had a positive PCR result on day 10 (Molina et al., 2020). An ongoing double blind RCT of patients with severe COVID-19 (NCT04323527) randomized 81 patients into high dose HCQ (600 mg 2x/d for 10 days) or low dose (450 mg/day for 5 days) treatment groups (Borba et al., 2020). Recruitment into the high dose arm was halted prematurely due to poor safety outcomes. There was no significant difference in negative PCR results on day 4 or need for mechanical ventilation on day 6. Taken together, the clinical trials performed thus far to evaluate the efficacy of HCQ ± AZ for COVID-19 have not demonstrated clear evidence of clinical benefit in patients with severe disease. A search of ClinicalTrials.gov on April 27, 2020 found 140 clinical trials investigating HCQ. This number is rapidly growing, indicating the heightened interest in this therapeutic and pressing need for evidence-based recommendations.

I’ve asked a number of questions about corticosteroids online and have gotten conflicting responses. My partner, who got sick after flying from the Bay Area in mid February, was prescribed prednisone after developing shortness of breath. She was tested twice for the flu. The first time came back negative and the second time, 5 days later, came back positive for Flu A (H1N1). I have been wondering whether people with COVID-19 are being treated with corticosteroids – possibly without having a confirmed COVID-19 diagnosis. To avoid missing or misinterpreting, the full quote from the paper follows:

Because of their anti-inflammatory activity, corticosteroids (CS) are an adjuvant therapy for ARDS and cytokine storm. However, the broad immunosuppression mediated by CS does raise the possibility that treatment could interfere with the development of a proper immune response against the virus. A meta-analysis of 5,270 patients with MERS-CoV, SARS-CoV-1, or SARS-CoV-2 infection found that CS treatment was associated with higher mortality (Yang et al., 2020c). A more recent meta-analysis of only SARS-CoV-2 infection assessed 2,636 patients and found no mortality difference associated with CS treatment, including in a subset of patients with ARDS (Gangopadhyay et al., 2020). Other studies have reported associations with delayed viral clearance and increased complications in SARS and MERS patients (Sanders et al., 2020). In fact, the interim guidelines updated by the WHO on March 13, 2020 advise against giving systemic corticosteroids for COVID-19 (World Health Organization, 2020a). Yet, new data from COVID-19 are conflicting.

One group reported no significant difference in time to viral clearance between patients who received methylprednisolone orally (mild disease) or IV (severe) and those who did not (Fang et al., 2020). Retrospective studies from groups in China report that patients who were transferred to the ICU were less likely to have received CS (Wang et al., 2020b) and that patients with ARDS who received methylprednisolone had reduced mortality risk (Wu et al., 2020a). In contrast, another retrospective analysis found that patients who received CS were more likely to have either been admitted to the ICU or perished, although the CS treated group also had significantly more comorbidities

(Wang et al., 2020c). A smaller observational study of 31 patients found no association between corticosteroid treatment and time to viral clearance, length of hospital stay, or symptom duration (Zha et al., 2020). A larger study of adjuvant CS in 244 patients with critical COVID-19 found no association with 28-day mortality; subgroup analysis of patients with ARDS found no association between treatment with CS and clinical outcomes (Lu et al., 2020b). They also found that increased dosage was significantly associated with increased mortality risk. A retrospective review of 46 patients, of whom 26 received IV methylprednisolone, found that early, low-dose administration significantly improved SpO2 and chest CT, time to fever resolution, and time on supplemental oxygen therapy (Wang et al., 2020h). Others have published perspectives in support of early (Lee et al., 2020) and short-term, low dose administration (Shang et al., 2020) based on anecdotal evidence, but not clinical trials. Most of the current data on CS use in COVID-19 are from observational studies, and support either modest clinical benefit or no meaningful effects. Larger RCTs are necessary to understand the risks and benefits of CS for these patients; there are 22 trials evaluating various corticosteroids registered on ClinicalTrials.gov as of April 27, 2020.

The authors next discussed therapies directed at cytokines and discussed cytokine blockade. Some interesting quotes:

Hyperinflammatory responses and elevated levels of inflammatory cytokines, including interleukins (IL)-6, 8, and 10, have been shown to correlate with COVID-19 severity.

The drivers of this cytokine storm remain to be established, but they are likely triggered initially by a combination of viral PAMPs and host danger signals.

The heterogeneous response between patients suggests other factors are involved, possibly including the SARS-CoV-2 receptor, ACE2.

Regarding clinical trials:

The commercial anti-IL-6R antibodies tocilizumab (Actemra) and sarilumab (Kevzara), and the anti-IL-6 antibody siltuximab (Sylvant), are now being tested for efficacy in managing COVID-19 CRS and pneumonia in 13 ongoing clinical trials.

To date, only one group has reported preliminary results from a cohort of 20 COVID- 19 patients treated with a single administration of tocilizumab (400 mg, IV), along with Lopinavir, methylprednisolone, and oxygen therapy (ChiCTR2000029765).

A second report described an association between use of tocilizumab and reduced likelihood of ICU admission and mechanical ventilation.

Other therapies discussed are neutralizing antibodies and convalescent plasma therapy. A SARS-CoV-2 neutralizing antibody was found out of 25 different antibodies isolated from the memory B cells of a survivor of SARS-1. Seven additional of the 25 were found to bind, but not neutralize. Regarding convalescent plasma (CP) therapy:

Despite the current lack of appropriately controlled trials, CP therapy has been previously used and shown to be beneficial in several infectious diseases such as the 1918 influenza pandemic (Luke et al., 2006), H1N1 influenza (Hung et al., 2011), and SARS-CoV-1 (Arabi et al., 2016).

CP therapy has also been proposed for prophylactic use in at-risk individuals, such as those with underlying health conditions or health care workers exposed to COVID-19 patients. The FDA has approved the use of CP to treat critically ill patients (Tanne, 2020). Determining when to administer the CP is also of great importance, as a study in SARS-CoV-1 patients showed that CP was much more efficient when given to patients before day 14 day of illness (Cheng et al., 2005b), as previously shown in influenza (Luke et al., 2006). This study also showed that CP therapy was more efficient in PCR positive, seronegative patients.

Finally, the authors discussed vaccine development. Some key points from this discussion are:

Although vaccination has a long and successful history as an effective global health strategy, there are currently no approved vaccines to protect humans against coronaviruses (André, 2003).

Previous work after the SARS-CoV-1 and MERS- CoV epidemics has provided a foundation on which many current efforts are currently building upon, including the importance of the S protein as a potential vaccine.

While the S protein has been found to be the most immunodominant protein in SARS- CoV-2, the M and N proteins also contain B and T cell epitopes, including some with high conservation with SARS-CoV-1 epitopes (Grifoni et al., 2020).

Regarding the vaccine pipeline:

For SARS-CoV-1 and MERS-CoV, animal studies and phase I clinical trials of potential vaccines targeting the S protein had encouraging results, with evidence of nAb induction and induction of cellular immunity (Lin et al., 2007; Martin et al., 2008; Modjarrad et al., 2019).

These findings are being translated into SARS-CoV-2 vaccine development efforts, hastening the progress drastically.

The University of Pittsburgh is also looking to move their microneedle array vaccine candidate containing a codon-optimized S1 subunit protein into clinical trials (Kim et al., 2020).

Although some of these vaccine candidates are based on platforms that have been used or tested for other purposes, there remain questions regarding their safety and immunogenicity, including the longevity of any induced responses, that will require continual evaluation.

Challenges and concerns regarding vaccine development:

One such concern involves the accumulating data supporting the initial assessment that COVID-19 is disproportionately severe in older adults. In conjunction with the large body of work related to immune-senescence, these findings indicate that vaccine design should take into consideration the impact of aging on vaccine efficacy (Nikolich-Žugich, 2018).

Furthermore, questions remain regarding the possibility of antibody-dependent enhancement of COVID-19, with in vitro experiments, animal studies, and two studies of COVID-19 patients supporting this possibility (Cao, 2020; Tetro, 2020; Zhang et al., 2020a; Zhao et al., 2020a).

Assuming vaccine candidates are identified that can safely induce protective immune responses, additional major hurdles will be the production and dissemination of a vaccine.

The concluding remarks of the authors include these notable ones:

The pathology of severe cases of COVID-19 do indeed resemble certain immunopathologies seen in SARS-CoV-1 and MERS-CoV infections, like CRS.

However, in many other ways, immune responses to SARS-CoV-2 are distinct from those seen with other coronavirus infections.

Significant proportions of individuals are asymptomatic despite infection.

SARS-CoV-2 has a longer incubation period and higher rate of transmission than other coronaviruses.

It is imperative that immune responses against SARS-Cov-2 and mechanisms of hyperinflammation-driven pathology are further elucidated to better define therapeutic strategies for COVID-19.

Since Figure 6 was used above, here is the description from the paper for Figure 6:

Figure 6. Available therapeutic options to manage COVID-19 immunopathology and to deter viral propagation.
A. Rdrp inhibitors (Remdesivir, Favipiravir), protease inhibitors (Lopinavir/Ritonavir), and anti-fusion inhibitors (Arbidol) are currently being investigated in their efficacy in controlling SARS-CoV-2 infections. B. CQ and HCQ increase the pH within lysosomes, impairing viral transit through the endolysosomal pathway. Reduced proteolytic function within lysosomes augments antigen processing for presentation on MHC complexes and increases CTLA4 expression on Tregs. C. Antagonism of IL-6 signaling pathway and of other cytokine-/chemokine-associated targets has been proposed to control COVID-19 CRS. These include secreted factors like GM-CSF that contribute to the recruitment of inflammatory monocytes and macrophages. D. Several potential sources of SARS-CoV-2 neutralizing antibodies are currently under investigation, including monoclonal antibodies, polyclonal antibodies, and convalescent plasma from recovered COVID-19 patients.
Abbreviations: GM-CSF, granulocyte-macrophage colony-stimulating factor; CQ, chloroquine; HCQ, hydroxychloroquine; RdRp, RNA-dependent RNA polymerase.

 

 

Author: J. Sands Loch

Student and teacher of reality in all its forms. I self-published my personal experience of discovering and trying to understand and use a model of reality based on the Many Worlds Interpretation of Quantum Mechanics: Surfing the Multiverse: Finding Happiness One Universe at a Time Available on Kindle and from Amazon, and found in blog post form at: SurfingTheUniverse.com

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