Developing an #mRNA vaccine is a sure-shot way to success? No! Despite the spectacular performance of #Pfizer & #Moderna vaccines, we also have a #CureVac fiasco. We need to dig in much deeper into the intricacies of developing a highly efficacious mRNA vaccine 1/
There is more than low dose & impact of VOCs behind #CureVac’s failure. And here we once again need to salute the sheer brilliance of @kkariko . Will do a little thread to explain, why! 2/
No doubt, the #CureVac used a much lower #RNA dose. Dose is lower (12 (CureVac) vs 30 (#Pfizer) vs 100 ug (#Moderna)) but no idea how that translates to protein. Need to know how much of a role the lower dose played in the lower efficacy 3/
#CureVac also employed ‘2P’ substitution to fix spike protein in prefusion conformation. 4/

However, the one key difference was they used unmodified #mRNA unlike other two mRNA vaccines. The idea was that the natural, unmodified RNA's higher reactogenicity would correlate with immunogenicity and allow the same protection at a lower dose. Apparently, it does not 5/
Animal study of #CureVac induced high NAbs. But Phase 1 induced #NAbs that were ~equal to convalescent compared to several times higher for the #Moderna & #Pfizer doses. It tells us that the problem is with the RNA, the lipids, or both 6/…
Now, the main #CureVac used #uridine instead of #m1Ψ (1-methyl-pseudouridine) in their unmodified mRNA... & likely to accidentally hit #TLR before the #Ribosome that way & wind-up w/ translational shutdown via phosphorylation of IFN2α after induction of ISGs.. 7/
So, probably their product induced too much type-I #IFNs when trying to translate #mRNA. Their immunogenicity data missed checking for IFN induction? 8/
Here, I need to insert some sort of explanation regarding the '#Uridine' & '#Pseudouridine'. The normal RNA characters are A,C,G and U. U is also known as ‘T’ in DNA 9/ ImageImage
#mRNA molecules are single-stranded slithers of genetic code formed of #nucleosides which instruct the human cells to produce certain proteins. However, for years there was a stumbling block: mRNA caused an inflammatory reaction when injected 10/
Another problem was that #synthetic mRNA was notoriously vulnerable to the body’s natural defenses, meaning it would likely be destroyed before reaching its target cells 11/
It wasn't until 2004 that @kkariko and her colleague
@DrewWeissman found that, by using a slightly altered #nucleoside in the mRNA string, the potentially fatal problem could be overcome 12/

So, in the #Pfizer & #Moderna vaccines, every U has been replaced by 1-methyl-3 pseudouridylyl (Ψ). The really clever bit is that although this replacement placates (Calms) our immune system, it is accepted as a normal U by relevant parts of the cell 13/… Image
This was a master stroke by @kkariko & @DrewWeissman to use m1Ψ instead of uridine to ‘dodge’ the immune system. And may be the main reason for the success of Pfizer & Moderna vaccines but failure of CureVac 14/…
This is the reason why she is considered as a front runner for #Noble prize in Medicine or Chemistry. CureVac incident has made her claims stronger. It was sheer brilliance, hard work & perseverance that paid off in long run 15/
Those of you wish to go for further details on the issue of Uridine vs Pseudouridine trick, an interesting blog shall be quite useful 👇 16/…
Some explanation: #Uridine is detected by TLRs, interferons are activated, and this prevents protein translation/expression. Less expression, less spike, less Antibodies, right? And #m1Ψ dodges the innate immune system & go unnoticed
Some of the tweets are based on the discussion by the #coronavirologist
@wanderer_jasnah 👇 17/

So, what are the takeaways?

For a successful #mRNA vaccine, you need:
➡️ A proper dose (to modulate adequate immune response & limit excessive innate activation)
➡️ Use ‘Synthetic’/’Modified’ mRNA (Ψ substituting U to avoid innate immune sensors)
➡️ Stabilize 'spike' (2P) 18/ Image
➡️ Proper purification & delivery systems (encapsulated into LNPs- protect RNA against potential digestion by ribonuclease)
➡️ Thermostability
➡️ To reduce doses & longer duration of immune responses, you may need ‘self-amplifying” RNA vaccine
#Gennova 19/end

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More from @vipintukur

19 Jun
#Spike protein’ is the major target of #NAbs in infected/vaccinated people. The prefusion conformation of the Spike represents the most relevant target because Abs can successfully interfere w/ infection only if they prevent binding to target cells or prevent fusion itself 1/
Various approaches are adopted to express ‘#Spike’ protein in vivo, such as nucleic acid structures & virus vectors. Alternatively, other vaccine platforms like recombinant protein particles & inactivated vaccines can directly deliver this protein 2/
Most structural studies of the wild-type spike protein exhibited one #RBD in the 'open' conformation. By contrast, 2 or 3 RBDs were observed in the open conformation in the more infective #D614G mutant--the RBD #conformation plays a vital role in the infectivity of SARSCoV2 3/
Read 16 tweets
14 Jun
In the #US & #Mexico trial of #Novavax vaccine (where 50% were #Alfa variant), it shows an overall efficacy of 90.4% & 100% efficacy against moderate or severe disease, on par with the vaccines made by Pfizer-BioNTech and Moderna…
“Novavax may be used as a booster in the U.S., but it’s certainly will be the first vaccine a lot of people are going to see around the world”
#Novavax new booster vax against #Beta variant is also found highly immunogenic in #baboon studies. A strong anamnestic response was demonstrated in baboons boosted with rS-B.1.351 approximately one year after immunization with #NVXCoV2373 (rS-WU1)…
Read 6 tweets
14 Jun
#DELTA DIARY: It is clear we are now dealing with a virus that spreads far more easily - probably more than twice as easily - as the version that emerged in #Wuhan at the end of 2019 1/…
The #Ro was around 2.5 when the pandemic started in Wuhan and could be as high as 8.0 for the Delta variant 2/
DELTA is evolving: A new, more genetically diverse cluster, lineage AY.1 (which is termed as #Delta+) with a new spike substitution #N417K having immune escape property, has emerged independently in some countries @vinodscaria 3/
Read 9 tweets
13 Jun
After almost 6 months of global rollout of #Covid19 vaccines, we have some data to assess their comparative efficacy/effectiveness. There seems to be a gradient in their performances:
*Best performing: BNT162b2 (Israel, US & UK) & Moderna’s mRNA & Sputnik-V (Bahrain) 1/
*Moderately effective: #AstraZeneca (UK), #JNJ (US, data still evolving)
*Modestly effective: #Sinovac’s CoronaVac (Chile, Brazil, Uruguay, Middle East) #Sinopharm’s inactivated (Seychelles, Mongolia) 2/
But on safety front, the #inactivated vaccines have scored over all others, both on reactogenicity front & as far as rare, serious AEFIs are concerned 3/
Read 5 tweets
5 Jun
What does #HerdImmunity mean in context with #SARSCoV2?
We don’t need the entire population to be vaccinated or the vaccines to be 100% effective (they never are); we just need them to reduce infection rates enough to get us <1. That is herd immunity 1/…
The issue is more complex. Despite achieving high seropositivity in certain regions, resurgences have occurred. And in certain regions/countries, the virus suddenly retracted even in the absence of a significant sero-positivity 2/
It is not a pure mathematics. There is an interplay of infection or vaccine-induced immunity & the evolution in the virus. The 'Ro' is not a fixed number--keep on changing with the virus transmissibility. With this changes the thresholds to achieve 3/
Read 6 tweets
4 Jun
How did #India fare? The graphic tells the whole story:
➡️Brutal onslaught by #B16172: having the highest transmissibility & most immune evader of all VOCs with higher virulence?
➡️No support from Vaccination (negligible coverage & high breakthrough, but reinfections rare) 1/
➡️ Social mitigation measures worked! Or the virus ran out of steam? Or still too early to conclude?
➡️ India struggled (significant mortality/health infrastructure collapsed) but survived!! 2/
New study on immune escape potential of #B16172 in comparison to #B1351 w/ #BNT162b2 vaccine: More immune evader than even B1351 VOC! Significant loss of antibody neutralisation vs live B16172 (-5.8x, akin to B.1.351) @TheLancet 3/…
Read 6 tweets

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