28 April Vaccines and more

Dear colleagues,

As some of you know, it has been a busy weekend, reviewing proposals for a special “COVID FWO call”. In addition, I had to prepare a short talk on vaccines that I presented this morning in the university of Hyderabad. 

I include the presentation with the accompanying, some that you may have seen already but also some new ones: 

Clearly, there are 6 platforms for SARS-CoV-2 today:

• The very classical concepts: inactivated and attenuated whome virus
• Recombinant vaccines of Spike : either plasmid DNA itself, the messenger RNA, the recombinant protein or a viral vector with inserted S.
• The inactivated is being developed by Chinese group and goes to phase ½
• The mRNA is being developed by Moderna (US) and Curevac (Germany)

1. The paper by van Dorenmalen illustrates the concept that Oxford is working on: a recombinant chimp Adenovirus with an S insert, in this case from MERS, but they have a similar construct from SARS-CoV-2.  Clearly, this looks promising as two shots could completely protect the rhesus macaques, as nicely shown in Fig 3 p. 8.  There was also cross-protection against several MERS strains in a mouse model (Fig  6 p.14).  Looks really§ promising as a platform.

2.  There is also this very nice paper by Jiahua He et al, which analyzes the molecular differences between the Spike and receptor-binding-domain of SARS-CoV-1 and SARS-CoV-2.  Unfortunately, I cannot critically judge their experiments, but the concluding messages are appealing.  SARS-CoV-2 Spike has:
   1. Lower free energy → hence more stable  ?
   2. Higher binding affinity for ACE2 → more infectious?
   3. Higher flexibility, therefore must overcome a higher entropy penalty to bind ACE2 

→  Flexibility may render development of drugs and vaccines more difficult

→  More temperature-sensitive than SARS-CoV-1 in human infection: may decrease infectious ability with the rising temperature, but come back in winter

3. Amongst the six platforms to develop a SARS-CoV-2 vaccine, the least attractive, at first view, is of course “live attenuated SARS-CoV-2”.  Nevertheless, there is an Indian group working on it. It is based on “codon pair deoptimization”, a process to maximize the number of codon pairs that are underrepresented in the protein coding sequences of the virus host. In that way, the virus remains the same, but it is just much less produced and crippled.   If it works, it would not be possible for the virus to “revert”, as is the case in classical attenuation by multiple passages in vitro.  See last paper.

Best wishes,

Guido