25 Jan 2023 Episode 310: Life cycle, BA.1 bivalent vaccine, MISC and myocarditis, cross-reactivity and PASC

Dear colleagues,

At first view a “mixed topic” episode, although you will that some seemingly unrelated topics are touching each other…

But first, a really beautiful and very didactic animation on the life cycle of SARS-CoV-2 from colleague Peters from Maastricht University https://www.maastrichtuniversity.nl/news/coronavirus-life-cycle-portrayed  Please check it out and use it for didactic purposes with due acknowledgments.

Par 1 Comparing BA.1 and BA.5 Bivalent vaccines

Ep 310-1: Andersson medRxiv 19 Jan in Scandinavia

• Either bivalent BA.4-5 or BA.1 mRNA-booster vaccines as a fourth dose was associated with increased protection against Covid-19 hospitalization and death during a period of BA.4-5 predominance.
• Bivalent BA.4-5 boosters conferred moderately greater vaccine effectiveness against Covid-19 hospitalization compared with bivalent BA.1 boosters.

 

 

 

 

These data confirm that a fourth dose is useful, irrespective of the type of bivalent vaccine.  However, we are now -again- in a new phase with even more “neutralization-resistant” variant such as BQ.1 and XBB.1.5…. 

 

Par 2 Pathogenesis of MISC and post-vaccination myocarditis

Ep 310-2: Sacco Nat Med May 2022: comparison of multisystem inflammatory syndrome in children (MISC) with regular pediatric COVID (pCOVID)

 

• pCOVID-19 was characterized by robust type I interferon (IFN)
• MISC:  
  • Prominent inflammatory markers (type II IFN-dependent and NF-κB-dependent signatures, matrisome activation)
  • Increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission.
  • Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation.
  • The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility.
  • MIS-C B cells showed higher mutation load than pCOVID-19 and pediatric healthy controls, but there is NO evidence of increased auto-antibodies

 

 

 

 

Expanded TCR BV 11-2: suggestive of a reaction to a “super-antigen” within abundantly circulating Spike (C-terminal of S1), in relation with a particular HLA constitution: HLA A*02, B*35 and C*04.

 

 

B cells in MISC show somatic hypermutation = evidence of rapid “maturation”, adaptation to circulating antigen, but no convincing evidence of auto-antibodies: rather directed towards SARS-CoV-2.

 

Ep 310-3: Yonker Circulation Jan 2023 Circulating Spike Protein in Post–COVID-19 mRNA Vaccine Myocarditis

 

 

 

1. Clear-cut increase of in inflammatory cytokines (as could be expected in myocarditis)

 

 

 

Remarks:            

- Type II IFN (gamma) increased, but type 1 (alpha-beta) not mentioned

- “Anti-inflammatory” IL-10 increased, but Th2 IL-4 decreased and IL-5 rather increased

 

2. No difference in  various antibodies

 

 

 

Overall antibody levels to Spike (A) and receptor-binding domain (B) indistinguishable with controls;

But also functional characteristics such as binding to various FcR (= receptors for the constant part of IgG in C) and effector functions such as antibody-dependent complement deposition (ADCD), neutrophil phagocytosis (ADNP), and cellular phagocytosis (ADCP) in D

 

Moreover, no evidence of increased auto-antibodies or any difference in Ab against common viral infections (coxsackie, herpes etc) – not shown here, see Fig 2

 

3. Remarkable increase in circulating Spike antigen

 

 

 

This Spike antigen increase is reminiscent of MISC, but MISC is associated with higher CRP and lower Troponin than post-vaccine myocarditis.

 

 

 

Ep 310-5: Pascal Irrgang Science Immunology Dec 2022: Class switch towards non-inflammatory, spike-specific IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination

 

 

This paper confirms that a third (wild-type) mRNA vaccine increases the neutralizing Ab against both WT and Omicron, as expected, but other Fc mediated effector functions such as Ab-dependent complement mediated phagocytosis (ADCP) and Ab-dependent complement deposition actually decreases after the mRNA booster, as a consequence of a strong increase in IgG4 class of antibodies, which do not efficiently mediate these Fc-receptor mediated functions.  It remains to be determined whether these functions are important in the antiviral effect, but it is an indication that repeated mRNA vaccination may have unwanted effect…

 

Par 3 Significance of cross-reactivity

 

As you may have noticed, it is not my favored topic, because expectations and even emotions of various actors are high, with some hoping that cross-reactivity between common-cold Coronaviruses and SARS-CoV-2 could explain why some people are more or less vulnerable to SARS-CoV-2, while, in fact, the literature is very confusing and contradictory….  

 

Ep 301-5: Sam Murray Nat Rev Immunol Dec 2022: trying to bring some order in this field

 

 

 

This overview picture explains why cross-reactivity with common-cold Coronavirus (cc-CoV)may sometimes be beneficial and otherwise detrimental for susceptibility to SARS-CoV-2 infection and disease.

It looks very complicated, but the crucial distinguishing element is “avidity” ( = functional affinity) of the receptors on T and B cells (the latter having thev  same antigen-binding motif as the secreted Ab).

• If the cross-reactivity has a high “avidity”, because of close relationship between the recognized antigenic determinant on the cc-Cov and SARS-CoV-2, they will be beneficial
• If this cross-avidity is low, chances are that it doesn’t matter or that it is detrimental, because they do bind to the antigen on SARS-CoV-2, but do not elicit strong effector functions.

 

Table 1 provides some examples

 

 

As can be seen, cross-reactivity at the T cell level is more likely beneficial, while the picture for antibodies is very mixed.  The explanation for this difference is simple: T cell epitopes are more conserved than Ab epitopes: as we know, the main function of Ab is “neutralization” by binding to the highly variable Spike.

Hence, the expectation that cross-reactivity  may be more important in preventing severe disease (by T cells acting against infected cells) than to prevent infection (which is dependent on neutralizing Ab)

 

However, those are very general statements.  Individual factors can modify the outcome very much:

• Genetic factors determine (via HLA and other genes) which epitopes each person recognizes and this will determine also the degree and avidity of cross-reactivity
• Old age, co-morbidities and immune suppression can further undermine the “beneficial” effects of cross-reactivity and probably even reverse them into (low-avidity) detrimental effects….

 

For more details and lots of interesting references, please read this interesting review.

 

Ep 310-6: J. Herman medRxiv 22 Sept 2022: Impact of cross-coronavirus immunity in post-acute sequelae of COVID.

 

Cohort of patients with pre-existing rheumatic disease: either developing or not PASC (= long-COVID):

 

Individuals with PASC:   

• harbored less inflamed and weaker receptor binding anti-SARS-CoV-2 antibodies and a significantly expanded and more inflamed antibody response against endemic Coronavirus OC43
• generated more avid IgM responses and developed an expanded inflammatory OC43 S2-specific Fc-receptor binding response, linked to cross reactivity across SARS-CoV-2 and common coronaviruses.

 

These (complicated) observations are interpreted in the context of “imprinting” (= “original antigenic sin”): pre-existing Ab to OC43 are rescued by SARS-CoV-2 infection and “deviate” the immune response to OC43 rather than to SARS-CoV-2, resulting in less efficient immunity to SARS-CoV-2 and thus facilitating long-COVID/PACS.

 

At present, it is unclear whether these observations in subjects with pre-existing rheumatic disease can be extrapolated to other patients… But, it is a nice illustration how cross-reactivity may have unexpected effects…

SOME CONCLUSIONS

 

1. BA.1 bivalent vaccine had a good level of protection against severe outcome of BA.5 infections in Scandinavia, just slightly less than BA.5 bivalent vaccine.
2. Both MISC (hyper-inflammatory reaction to COVID) and myocarditis after vaccination are characterized by presence of free Spike antigen in circulation.  Are there other genetic (e.g. HLA) and immune (e.g. super-antigen reactions) resemblances to be discovered?
3. There is increasing interest in “Fc-receptor-mediated” effector functions  (complement activation, phagocytosis…) in pathogenesis and protection after infection and vaccination, but the picture is not clear yet.
4. Cross-reactive immunity between common cold CoV and SARS-CoV-2 is a very real phenomenon, but many variables determine the beneficial or detrimental consequences: e.g. T cells more likely beneficial than Ab, precise epitopes, genetics and other factors (age, immune suppression) determine outcome.    

 

Best wishes,

 

Guido