28 July Vaccination antibody-dependent enhancement reinfection and evolution ADE part 1

Tue, 07/28/2020 - 22:18
  1. Interesting pre-clinical vaccine candidates
  • DNA vaccine: various S constructs (see Fig 1) could induce protection against disease after 2 immunizations and challenge with homologous challenge (the same virus that was used for the vaccine constructs).  The full S construct was the best immunogen. The immunity was not sterilizing. Neutralizing antibodies, but also other effector functions (activation of monocytes and NK cells) have a role.  
  • Two papers, using self-amplifying (sa) RNA immunogenicity vaccine in mice and (for the second one) also in non-human primates.  In these cases the RNA code for Spike proteins from Wuhan (similar, but not the same as in the DNA vaccine) is integrated as a “subgenomic RNA” in a alphavirus vector (VEEV).  Clearly, this will produce an (abortive) viral infection and a lot of mRNA in vivo (in contrast with the “simple” mRNA from Moderna and BioNtech- see mail of 23 July.  All these RNA species have to be formulated in “lipid nanoparticles” to protect them against RNases and enhance release from endosomes.  

Both saRNA are quite immunogenic, can be used in prime-boost, induce substantial neutralizing antibodies and T helper 1  responses. The second paper provides more convincing data: in non-human primates and in young versus old mice.


  1. Antibody-dependent enhancement: there is evidence from SARS and MERS in experimental in vitro and animal (including primate) models that antibodies, induced by infection (passive transfer) or vaccination could aggravate symptoms after infection. 

This could be the case for SARS-CoV-2 e.g. during a second or third wave or after vaccination, but would presumably require a sufficient degree of “antigenic drift or shift” (by mutation or recombination, i.e. occurrence of new “strains”).  

The tendency to ADE is presumably dependent on host genetics i.e. polymorphism in the FcRgamma II (receptor for IgG) and could also depend on which IgG subtype is preferentially induced, the affinity and concentration of the anti-S antibodies.

Although cross-reactivity, especially at the level of T cells, has been shown between “common” beta-coronaviruses and SARS-CoV-2, there is, as yet, no clear evidence that this could have a role in the severity of disease in some, but not other individuals, although I’m not aware of studies that have investigated this issue formally. Could be a nice research project, but then best in combination with anti-SARS-CoV-2 antibodies.

  1. Fading immunity: after infection is now well established, at least in term of declining antibody titers, including neut. See figure p. 19 in the medRxiv preprint from King’s College. Clearly, SARS-CoV-2 neutralizing antibodies after natural infection do not persist very long.


  1. Hence: reinfection possible? ” The jury is still out”, as they say
  • In macaques, it was not possible to induce a productive re-infection, but this was only 4 weeks after initial infection and with homologous virus.
  • In humans, there are a number of reports of prolonged or re-appearance of positive RT-PCR, but, until now, very littke evidence of true “recurrence” or “new infection


  1. Viral mutations and evolution: is clearly happening.  See several reports.  Obviously, the degree of viral evolution (mutations, but also recombination) will determine the chances of re-infection, ADE and vaccinal success on the longer run…..