Two Different Antibody-Dependent Enhancement (ADE) Risks for SARS-CoV-2 Antibodies

Abstract

COVID-19 (SARS-CoV-2) disease severity and stages varies from asymptomatic, mild flu-like symptoms, moderate, severe, critical, and chronic disease. COVID-19 disease progression include lymphopenia, elevated proinflammatory cytokines and chemokines, accumulation of macrophages and neutrophils in lungs, immune dysregulation, cytokine storms, acute respiratory distress syndrome (ARDS), etc. Development of vaccines to severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome coronavirus (MERS-CoV), and other coronavirus has been difficult to create due to vaccine induced enhanced disease responses in animal models. Multiple betacoronaviruses including SARS-CoV-2 and SARS-CoV-1 expand cellular tropism by infecting some phagocytic cells (immature macrophages and dendritic cells) via antibody bound Fc receptor uptake of virus. Antibody-dependent enhancement (ADE) may be involved in the clinical observation of increased severity of symptoms associated with early high levels of SARS-CoV-2 antibodies in patients. Infants with multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 may also have ADE caused by maternally acquired SARS-CoV-2 antibodies bound to mast cells. ADE risks associated with SARS-CoV-2 has implications for COVID-19 and MIS-C treatments, B-cell vaccines, SARS-CoV-2 antibody therapy, and convalescent plasma therapy for patients. SARS-CoV-2 antibodies bound to mast cells may be involved in MIS-C and multisystem inflammatory syndrome in adults (MIS-A) following initial COVID-19 infection. SARS-CoV-2 antibodies bound to Fc receptors on macrophages and mast cells may represent two different mechanisms for ADE in patients. These two different ADE risks have possible implications for SARS-CoV-2 B-cell vaccines for subsets of populations based on age, cross-reactive antibodies, variabilities in antibody levels over time, and pregnancy. These models place increased emphasis on the importance of developing safe SARS-CoV-2 T cell vaccines that are not dependent upon antibodies.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943455/

Philippines halts dengue immunisation campaign owing to safety risk

Rapid Response:

Dengue vaccine and influenza vaccine are both subject to increased illness risk via "antibody-dependent enhancement"

The Phillipine Dengvaxia scandal continues to unfold (NYT, WSJ, CIDRAP 12/18/17)…..Meanwhile it reminds us that influenza vaccines also increase the risk of illness via "antibody-dependent enhancement" of infection: some vaccines evoke antibodies that are poorly matched to circulating viruses; instead of neutralizing the viruses these antibodies enhance uptake of the viruses via Fc receptors on mononuclear phagocytes, which then manufacture large numbers of virus, leading to severe illness. This seems counterintuitive, but the phenomenon is quite real. In the third year of a randomized trial the risk of hospitalization from a dengue infection was 5-fold in young vaccine recipients. (Hadinegoro, NEJM 2015;373:1195. Halstead, Am J Trop Med 6/8/16)…..ADE helps account for the fact that the 2008-9 flu shot doubled the risk of illness from the 2009 H1N1 pandemic flu (Skowronski, PLoS Medicine 2010); the increased H1N1 illness risk in US children associated with the 2015-16 nasal flu vaccine (Jackson, NEJM 2017) ; and the 68% increase in H3N2 illness risk among UK elderly after the 2016-17 flu shot (Pub Health England 8/31/17).

Recent announcements that the 2016-17 flu shot was "only 10% effective " against H3N2 in Australia concealed the possibility that it increased the risk in the elderly by as much as 160%!! (VE minus 20%; minus 160 to 42). (Paules, NEJM 11/29/17. Sullivan, Euro Surveill 10/2617)

Influenza deaths do occur in vaccinated individuals, and some are likely the result of antibodies that enhance infections instead of neutralizing them. This is particularly worrisome as we wait for the next pandemic, possibly from the H7N9 virus that has emerged in China. (Skowronski, Euro Surveill 4/25/13)….Finally, one of the obstacles to the development of a universal influenza vaccine is the very real possibility of provoking ADE. (Jang, Viruses 2014;6;3159. Dutry, BMC Proceedings 2011; 5:suppl 1:P62)

https://www.bmj.com/content/359/bmj.j5759/rr

Keep in mind the cocktail being presented now most likely alters the Fc segment to reduce ADE.

Read that in one of the studies.

Structure-guided T cell vaccine design for SARS-CoV-2 variants and sarbecoviruses

Abstract

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that escape convalescent and vaccine-induced antibody responses has renewed focus on the development of broadly protective T-cell-based vaccines. Here, we apply structure-based network analysis and assessments of HLA class I peptide stability to define mutationally constrained CD8+ T cell epitopes across the SARS-CoV-2 proteome. Highly networked residues are conserved temporally among circulating variants and sarbecoviruses and disproportionately impair spike pseudotyped lentivirus infectivity when mutated. Evaluation of HLA class I stabilizing activity for 18 globally prevalent alleles identifies CD8+ T cell epitopes within highly networked regions with limited mutational frequencies in circulating SARS-CoV-2 variants and deep-sequenced primary isolates. Moreover, these epitopes elicit demonstrable CD8+ T cell reactivity in convalescent individuals but reduced recognition in recipients of mRNA-based vaccines. These data thereby elucidate key mutationally constrained regions and immunogenic epitopes in the SARS-CoV-2 proteome for a global T-cell-based vaccine against emerging variants and SARS-like coronaviruses.

https://pubmed.ncbi.nlm.nih.gov/34265281/

Inactivated SARS-CoV-2 vaccines unlikely candidates for undercutting spike-mutation variants of concern

https://www.clinicaltrialsarena.com/comment/inactivated-sars-cov-2-vaccines-unlikely-candidates-for-undercutting-spike-mutation-variants-of-concern/

And even if a vaccine features the whole SARS-CoV-2, mutations do not just happen in the spike protein but everywhere in the virus, Bottazzi added. >>14500742

MRI and Vaccination (graphene oxide) will cause a lot of problems.