10 August More on BCG TB, “trained immunity” and ADE

Mon, 08/10/2020 - 13:34
  1. The hypothesis that BCG may have a protective effect on COVID-19 related mortality becomes highly criticized.  A thorough analysis by Wassenaar et al finds no effect.  Miyasaka points to the difficulty of using various BCG strains, complicating the interpretation. Ricco et al have performed a meta-analysis with the provocative title: Stop playing with data.  Nevertheless, when you look at the summarizing data, many are in favor of a beneficial effect and some find no effect.  The authors suggest that there are many confounders, so no final conclusion is possible for now.  Clearly, as discussed previously, the ongoing clinical trials in HCW will  hopefully provide more conclusive data.


  1. An extension of the “trained immunity” hypothesis by Sherawat and Rouse to explain the presumed (but not proven) effect of BCG, stating

“… we surmise that frequent exposure of individuals to natural environmental microbes, live attenuated vaccines against other viruses or bacteria or certain natural ligands such as different types of lectins and saponins that can stimulate innate immune receptors all help to reduce the clinical consequences of COVID-19 infection”

Clearly, it is for sure that the state of the “innate immunity” (as the first line of defense against SARS-CoV-2) has a decisive role in the outcome of the infection. It is also well known that there are differences in innate immune reactions according to advanced age and comorbidities, both of which tend to be associated with an “pro-inflammatory” status, that acts as a negative factor (“refractoriness”) on appropriate innate  (and adaptive) immune responses. So this hypothesis is not really ground-breaking.  However, it will be even more difficult to prove or disprove this very broad hypothesis than the more focused BCG hypothesis.  A good scientific hypothesis has to be testable and therefore, you need to be more precise….  


  1. Negative impact of SARS-CoV-2 on TB.  In my previous mail, I indicated that the COVID measures in Taiwan seem to have had a beneficial  effect on new TB cases and that in South-Africa TB is a risk factor for COVID-related death.  In the paper by Addis Alene, an analysis is made how COVID could negatively impact on TB:
  • Lockdown of families will increase TB transmission and the effect will only become evident in the future (because of the long incubation time of TB) 
  • COVD infection could reactivate latent TB or increase susceptibility to new TB.
  • The overwhelming of health system decreases diagnostic, therapeutic and preventive capacity for TB
  • Worsening of economic situation will indirectly contribute to TB burden

A nice table with actions to counter these effects (p.5) 


  1. A very nice overview on ADE and SARS-CoV-2: some highlights
  • Most evidence for enhanced disease from children given formalin-inactivated respiratory syncytial virus (RSV) or measles vaccines in the 1960s, and in dengue haemorrhagic fever due to secondary infection with a heterologous dengue serotype


  • Four principles about ADE:
    • No predictive in vitro test
    • Animal models may be misleading
    • Protective and non-protective antibodies can be elicited to different forms of the same (viral) protein. (See formalin inactivation of RSV fusion protein  as a trigger for ADE )
    • Mechanisms of pathogenesis differ among (strains of ) viruses.


  • The mechanism of ADE of disease associated with dengue depends on three factors:
      • circulation of multiple viral strains with  variable antigenicity,
      • virus capable of replication in Fc.R-expressing myeloid cells,
      • sequential infection of the same person with different viral serotypes


  • …. Clinical experiences with RSV, influenza and dengue provide strong evidence that the circumstances that are proposed to lead to ADE of disease—including low affinity or cross-reactive antibodies with limited or no neutralizing activity or suboptimal titres-   are very rarely implicated as the cause of severe viral infection in the human host. Furthermore, clinical signs, immunological assays or biomarkers that can differentiate severe viral infection from a viral infection enhanced by an immune mechanism have not been established


  • Previous infection with HCoV-HKU1 and HCoV-OC43 betacoronaviruses, or HCoV-NL63 and HCoV-229E alphacoronaviruses, is not known to predispose to more severe infection with the related virus from the same lineage.  
  • Although HCoV-NL63 also uses the ACE2 entry receptor, the receptor-binding domain (RBD) of HCoV-NL63 is structurally very different from that of SARS-CoV-2, which would limit antibody cross reactivity.


  • The evidence that COVID-19 does not worsen after treatment with plasma from convalescent patients has been substantially reinforced by a study of 20,000

patients who were severely ill with the disease, showing an adverse event incidence of 1–3 % only.


  • “….  Current clinical experience is insufficient to implicate a role for ADE of disease, or immune enhancement by any other mechanism, in the severity of COVID-19.

Prospective studies that relate the kinetics and burden of infection and the host response—including the magnitude, antigen-specificity and molecular mechanisms of action of antibodies, antibody classes and T cell subpopulations—to clinical outcomes are needed to define the characteristics of a beneficial compared with a failed or a potentially detrimental host response to SARS-CoV-2 infection.

Although it will probably continue to be difficult to prove that ADE of disease is occurring, or to predict when it might occur, it should be possible to identify correlates of protection that can inform immune-based approaches to the COVID-19 pandemic


  • Nevertheless in animal models of SARS, enhanced disease has been shown after vaccination:
    • In the ferret model, modified vaccinia Ankara expressing S protein (MVA-S) was not protective and liver inflammation was noted
    • Enhanced disease was observed in mice that were immunized with formalin- or ultraviolet-inactivated SARS-CoV
    • Unlike SARS-CoV, MERS-CoV and SARS-CoV-2, feline infectious peritonitis virus is an alphacoronavirus that, like dengue, has tropism for macrophages. Infection with this virus has been shown to be enhanced by pre-existing antibodies, especially those against the same strain.
    • Formalin-inactivated SARS-CoV reduced viremia and protected against lung pathology in rhesus macaque in one study, whereas in another study macaques given FI-SARS-CoV developed macrophage and lymphocytic infiltrates and alveolar oedema with fibrin deposition after challenge, indicating the difficulties of establishing consistent NHP models.


  • In most animal models—including NHPs—vaccination or the administration of passive mAbs have demonstrated protection against challenge with SARS-CoV, MERS-CoV or SARS-CoV-2, although reports on SARS-CoV-2 are limited.

           However, studies of an Formalin)inactivated SARS-CoV vaccine, one of two studies of an MVA vaccine expressing SARS-CoV S protein, and vaccination with one S-derived peptide showed enhanced lung pathology in NHPs.

          Thus, there are limited data to indicate that immune responses that include antibodies (and probably also T cells) induced by some vaccine formulations may be associated with more extensive lung pathology compared with infection alone, whereas the        transfer of mAbs with specific properties have, so far, provided protection in animals.