5 April 2021 Episode 125 Vaccines and variants again and again

Mon, 04/05/2021 - 19:55

Dear colleagues,

It has been a bit of a hectic week, filled with voluntary teaching professionals on the ins and outs of COVID and candidate postdoc evaluations for FWO. And now, finally, on Easter Monday, I’m trying to catch up with COVIDology, while looking after my lovely grandsons (Maxim and Miles) and their cute puppy, named Flo. This is an interesting exercise that millions of young parents had to survive, while “working from home” during Corona times.  I feel like 30 years younger….  

Vaccine efficacy

Ep 125 1a: A CDC study on prevention of infection (tested weekly) by the Pfizer-BioNTech vaccine amongst 3950 HCW over 13 weeks.  In the almost 1000 unvaccinated subjects the incidence was 1.38/1000 PY; in 474 single vaccinated it was 0.19 and in 2,479 fully vaccinated 0.04.  This translates in a 80 % efficacy > 14 days after first dose and 90 %  > 14 days after the second dose.

In the BMJ comment (Ep 1251b), the remark is made: vaccination rates among doctors were 92%, nurses 82%, and first responders 64%, and the infection rates in these categories were

1.9% (doctors), 5.0% (nurses), and 8.8% (first responders). Interesting difference..?

 

Clearly, this study confirms earlier studies in UK and Israel on infection prevention by Pfizer.

 

Ep 125-2: an article in the NYT on the first efficacy data of Pfizer-BioNTech in 2260 adolescent (12-15 yrs). In the placebo group 18 cases of symptomatic infection versus none in the (fully?) vaccinated group. It is also said that these adolescents produced higher antibody levels than young adults (16-25).  Also Moderna, AZ en Janssen are testing their vaccines in children and adolescents.

 

Ep 125-3: a small Canadian study comparing the antibody responses to a single Pfizer dose:  clearly lower response in elderly, especially no in vitro neutralization of life virus by 1/20 serum dilution. The authors conclusion: don’t postpone the second dose.

 

Ep 125-4 confirms earlier data that the P1 (Brazilian) variant shows some level of resistance to monoclonal antibodies, convalescent serum and serum from individuals fully vaccinated by either Pfizer or Astra-Zeneca vaccine in various assays, including neutralization using life “Victoria” virus.  However, the B1.135 (South-African) variant is clearly more resistant.  Hence it is hoped that the present vaccines will protect against P1.  We know that the Novavax and Janssen vaccines protected only about 50 % in South-African trials and AZ showed very little protection, but apparently trial or “real world” data about protection against Brazilian P1 are still lacking….  

 

(Presumed) side effects:

 

Ep 125-4: Greinacher et al. summarize the 9 cases (8 women, 1 men 22-49 yrs old) of Prothrombotic Thrombocytopenic Disorder Resembling Heparin-Induced Thrombocytopenia Following Coronavirus-19 Vaccination, with the Astra-Zeneca vaccine.  This is a very rare condition, but it is clearly very serious (4 patients died) and difficult to predict (only 2 had a history of auto-immunity).  The causal relation may not be proven, but the timing is suggestive: 4-16 days after vaccination.  Very annoying for those who have to promote vaccination….

 

To put things into perspective:

 

Ep 125-5: reminds that up to 20 % of hospitalized COVID patients suffer from “cardio-embolic complications”.  The pathophysiology is discussed and it is proposed that binding of SARS-CoV-2 to endothelial cells is the first trigger, implying a role for the spike protein….

 

Ep 125-6 is a compilation of the incidences of potential adverse events of special interest for COVID-19 vaccines in the general population of eight countries.  Interestingly,  immune thrombocytopenia has an incidence of 10 (men) and 15 (women) per 100,000 person years in 35-54 years old  (Table 2 p. 10). 

 

Can someone make the calculation on how this relates to the 9 cases on x million AZ vaccinations?

 

More on variants:

 

Ep 125-7 is a thorough review on the main mutations in SARS-CoV-2 so far, arguing that 4 forces of evolution are involved:

  1. Increasing “fitness” (mainly focused on entry);
  2. Improving interaction of viral protein with human factors (including the interference with type 1 IFN);
  3. Escape for adaptive immunity (until now mainly focused on antibodies, but it will also apply to T cells;
  4. “Genetic” drift; “hitchhiking” and “founder effects”, where chance events play a major role

The paper explains in detail what we already understand, based on structural-functional knowledge and points to “convergent evolution”: the independent emergence of similar (combinations of) mutations in various parts of the world. It is very didactically illustrated.

 

Ep 125-8 and -9 speculate further on some of these phenomena and suggest that this may be a sign that the virus has only a limited set of possibilities to improve it’s adaptation to humans and hence it may -sooner or later- have exhausted these possibilities. 

 

We’ll see what will happen…..

 

Some interesting new vaccine candidates

 

Ep 125-10 presents a recombinant life-attenuated measles vaccine, developed by the Ohio State University: when prefusion S is used (the same construct as in the mRNA and Adeno vaccines), a single dose elicits very high neut titers as well as Th1 responses and a seemingly complete protection in the sensitive hamster model.

 

The next two pre-prints are based on ferritin nanoparticles: Ferritin is a naturally occurring, ubiquitous, iron-carrying protein that self-oligomerizes into a 24-unit spherical particle.

 

Ep 125-11: From a US consortium mainly at East Coast; a SARS-CoV-2 Spike protein ferritin nanoparticle vaccine, with conjugation to pre-fusion stabilized S protein and co-formulated with a liposomal adjuvant, elicits broad neutralizing antibody responses that exceed those observed for other major vaccines and rapidly protects against respiratory infection and disease in the upper and lower airways and lung tissue of nonhuman primates. Two doses are required for full effect.

 

Ep 125-12: From La Jolla.  They designed a different nanoparticle: S2GΔHR2 spike, which was displayed on three self-assembling protein  nanoparticle (SApNP) platforms, including ferritin (FR) 24-mer and multilayered E2p and I3-01v9 60-mers, as COVID-19 vaccine candidates. 

 

This construct is described in Ep 125-12 A (Sci Adv 19 March 2021): it is a fusion construct containing SARS-CoV-1/2 RBD, a short 5–amino acid G4S linker and a trimeric viral capsid protein.  A heptad repeat 2 (HR2) in S2 was deleted, because it was causing spike metastability, to an HR2-deleted glycine-capped spike (S2G-delta-HR2), and displayed it on SApNPs, shown below

 

Diagram of conjugating RBD to the 60-meric multilayered I3-01v9 SApNP using the SPY system. Locking domains (LDs) and T helper epitopes within the multilayered SApNP are depicted.

In this earlier paper this construct was shown to elicit high neutralizing Ab and T cell responses in mice.

 

In the more recent Ep 125 B (bioRxiv 28 March), they show that this construct elicits similarly high neut Ab in mice against the most prevalent “variants of concern,”, including the British, Brazilian and South-African (Fig 1 p. 30).  They explain this unusual strong and broad response by a prolonged lymph node retention and robust germinal centers stimulation.  

 

What it will take to vaccinate the world

 

Ep 125-13 A (Nature) focuses more on technical aspects and argues that companies are already working together to get the job done.  The demand for a waiver on IP rights is also discussed, but it is also emphasized that the technology to produce the “high tech” mRNA and Adeno vaccines cannot so easily be realized in a QC and GLP proof way. 

 

Ep 125-13 B focuses more on the enormous inequity and the pressing need to also vaccinate the vulnerable older population and health care workers in low income countries.  The impression that the pandemic is less severe in those countries is not real and partly explained by under-reporting.

Best wishes,

 

Guido  

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