328 - Vaccine progress | Scoins.net | DJS

328 - Vaccine progress

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Looking to classify approaches to viruses, I found several versions of a classification. I've opted for there being four classes, each divided into two [1, 2]

1 Virus Vaccines

1a  Live attenuated virus - a deliberate mutation of the original that pushes the body into appropriate defences.

1b  Inactivated virus - disable the target virus so it doesn't replicate; inject that to generate suitable defence response.

2 Viral vector - another route to causing the body to generate antigen. E.g. adenovirus.

2a Replicating viral vector e.g. measles

2b Non-replicating viral vector, e.g. adenovirus4 Protein based vaccines

3 Nucleic acid vaccines DNA and RNA vaccines, often labelled as mRNA, contain code for a coronavirus protein so the body generates antigen.

3a DNA vaccine, uses electroporation to cross cell membrane.

3b RNA vaccine in a lipid coat to cross the cell membrane.

4 Protein-based vaccines

4a Protein subunit (of the coronavirus antigen), which won't replicate but will stimulate defence.

4b Virus-like particles -VLP- resembles coronavirus in structure but include none of the genetic material.

________________________________

A little about how they work is at [3], where not already explained by [1] and [2].

When a vaccine is developed it goes through phases of testing [4] 

0. Preclinical, the plan, development, construction

1.  safety, dosage  small samples <100

2.  effectiveness, Phase 2 trials will be 3 and 4 digit sizes

3.  Phase 3 trials use large samples, typically 50k size

4.  approval and licensing, subsequent monitoring


An entirely different problem is delivery. Yesterday, 20201221, I noticed for the first time a prediction that delivery within the UK to those declared at-risk for any reason is predicted to take until July, not early May as I had been thinking. That means the herd immunity point might be as far away as September or even later. In turn that might well mean that, if the fear level continues much as it has done, we lose most of 2021 to consequences of 2020. It also means that on a global scale, her immunity may be much further off, maybe 2025. I wonder if this will have consequences for global travel. IN terms of carbon reduction, that is surely a good thing.

That awful tendency of the selfish to escape any restriction and, in so doing, to cause spread—which needs a pithy label, such as escape spreading—has a parallel in climate change reduction, where people who can so afford do more travelling while that is still permitted. Of course, those in the travel industry will encourage this, their parallel being to make sales while they still are able to, but all in all this pushes nations into having to regulate towards restriction rather than have people make sensible choices and restrict themselves. That too needs a pithy label.

I recognise in myself an assumption that the coronavirus pandemic will leave that virus as endemic, not eliminated. I see this as a consequence of the diesase being viral, which, I understand, is therefore likely to mutate and often. i wonder if a viral disease can be eradicated? [8] suggests that, whtever we think of 2020, this is not 'the big one' in terms of pandemics.



DJS 20201229

30th Dec: Astra-Zeneca's vaccine AZD1222 was approved by/for the UK (NYT says for emergency use only). Moderna is (we are told) close to approval in the US; Sinopharm announces efficacy of 79% for BBIBP-CorV.


Moderna vaccine cleared for use 20210108 but won't be available until late March or April. Therefore probably discounted from calculations as not immediate enough. Probably expensive, too.


[1] https://graphics.reuters.com/HEALTH-CORONAVIRUS/VACCINE/yzdpxqxnwvx/   middle school read. 

[2] https://www.nature.com/articles/d41586-020-01221-y offers categories 

[3]  https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/how-they-work.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fvaccines%2Fabout-vaccines%2Fhow-they-work.html

[4]  https://www.jnj.com/innovation/the-5-stages-of-covid-19-vaccine-development-what-you-need-to-know-about-how-a-clinical-trial-works

[5] https://covid19vaccinetrial.co.uk/phase-iiiii-trial-explained

[6]   https://en.wikipedia.org/wiki/COVID-19_vaccine

[7]  "COVID-19 vaccine development pipeline (Refresh URL to update)". Vaccine Centre, London School of Hygiene and Tropical Medicine. 11 December 2020. Retrieved 11 December 2020. Somewhat confusing, but worth the work to understand what's provided if you want detail.

[8] https://www.theguardian.com/world/2020/dec/29/who-warns-covid-19-pandemic-is-not-necessarily-the-big-one

[9] https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html#beijing   NY Times round up on the same topic as this page. I've opted for this source's tables, as they are updated more often. ----> Last NYT update 4th Jan.


Vaccines under construction: approved here and phase 3 below

In order of appearance (in the media, or if you prefer, as noticed by me);  

https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker          

https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines

Pfizer/BioNTech this is the one that has to be kept very cold, like -70ºC. Approved in the UK EU, 20201221 and the UK, earlier. 95% effective. mRNA type vaccine, which is new. Developed in the UK, Germany and mostly made in Belgium. Check this.   BBC report.

Moderna/NIAID, 95% effective in trials. Same mRNA approach, 5M doses ordered for UK. Kept at -20ºC. Approved in Canada 20201223, and US, later.

Oxford / Astra Zeneca either 70% or 90% effective, depending on delivery (so 90%, since obviously one will choose the more effective route). 100M UK doses ordered. AZ has this wonderful policy to supply to poor countries at cost. Long may they succeed. UK approved this on 20201230.

Russian Sputnik V, same approach as Oxford, 92% effective

Janssen has reached the mass testing stage. Adenovirus approach as Gamaleya, below) 

Novovax recombinant SARS nanoparticle vaccine with adjuvenant.

Wuhan, Sinopharm, Gamaleya as in the tables hereabouts. There are, as the WHO extract shows, 52 in clinical evaluation.

Guardian report.

Target: herd immunity is around the 70% mark of the global population. Which I reckon means we need to have inoculated 80% at 90% effectiveness. That is a huge target, bearing in mind the turnover of population. Just maintaining a position is a huge undertaking, let alone reaching the target. We have yet to discover the period at which boosters will be required. If this is more frequent than annually we have a whole new class of difficulty, possibly culture-changing. Pun intended.


Take WHO link to https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines, Download 12-page pdf. Some of page 1 reproduced above. This is updated frequently. 20201222 updte says 172 in pre-clinical development, a further 61 in clinical development. This is a spreadsheet that is updated quite often.  Sample table here -->.

This paper from 2013 suggests that only 22% of the initiatives were forecasted in 1996 to successfully reach the market after 10 years of development, and that the average vaccine, taken from the preclinical phase, requires a development timeline of 10.71 years and has a market entry probability of 6%. Which might suggest that of the 52, we could expect 3 to survive or for 11 to survive. Taking the more optimistic number (applying the 22% figure) then we should be able to look at some probabilities, which implies a whole extra page in the Maths section. For example, the probability we have only up to two successful vaccines from 11 reaching clinical trials is .78¹¹+11(.78)¹⁰(.22) + 55 (.78)⁹(.22)² = .551, that is, P(X≥3)=0.551

Similarly, that only up to 3 of the 52 reach completion at 6% success is 0.62, as shown here;

P(X≤3|X~Bin(52,0.06)) = 0.94⁵² + 52(0.94)⁵¹(0.06) + 1326(0.94)⁵⁰(0.06)² + 22100(0.94)⁴⁹(0.06)³ = 0.620

So the P(X>3) of more than 3 succeeding is 1-that = 0.38 and of more than two p(X≥3) succeeding is [...] 0.610

20201222 Sharon Peacock on the new variant. Good stuff.

The intended vaccination process within the UK aims to maximise the number of people covered. So instead of delivering two jabs at the optimum / expected interval of three weeks, that interval is increased to 12 weeks. This means that far more people—like twice as many—can be jabbed in the same period and, provided efficacy is over 50%, this is a win. Efficacy is thought to be in excess of 70% over this 12-week interval, so this is a significant win. Presumably at 12 weeks the effort goes into second jabs so that the bigger number of who has been declared as at-risk is boosted to much longer-term cover. Meanwhile the under-16s are not included in the licensing and the 16-50 group are considered not at risk. The impetus is driven by the understanding that the vaccine is very good at preventing the virus from serious illness, though we're not so very sure about infection rates. At 2M jabs delivered a week and starting at that volume from mid-Jan, we have 13 million 1st wave to include, so probably late February, with antibody counts significant three weeks later, say mid-March. The second round jabs for that group start mid-April (or sooner), so the 50-70 age-group (second wave along with non-medical key workers) may be jabbed at for the maybe six weeks between March and  the mid-April moment. Secondary jabs for the second wave begin in mid-July, so that the third wave, everybody else that wants a jab, runs whenever there is spare capacity. We expect the 2M per week to rise, perhaps as high as twice that. Of course, there comes a point at which demand from elsewhere takes precedence, so it seems to me quite likely that those considered at low risk continue to be uninoculated. It is also possible that by say June we have a wider range of working approved vaccines (not just in the UK, which produces approval relatively quickly) to choose from. What we still don't have is a good supply chain. I see this position changing; politically the need to be able to generate vaccine within our borders has been something I first identified in the March essay. I wrote then that  Apparently, Britain has no in-country facilities for generating vaccine stock. So that is poor security of supply, which is something we will see criticised around the world as the year goes by. See link (in the line above, August 2008) for comment on public sector vaccine manufacturing. It is apparent now that we have vaccine made by Astra Zeneca and in Oxford and Cobra Biologics in Keele; from bulk manufacture there is a pause while batches are tested for quality, something of a hold-up currently, then there is what is called 'filling and finishing', putting bulk vaccine into vials and labelling, which takes place in Wrexham and where we identify a mass shortage of the little glass bottles. I read that we have a new facility, VMICuk, under construction at Harwell, south of Oxford. Perhaps someone was reading my stuff, after all; more probable to have been like minds running in parallel. VMIC may even open in 2021.  “We repurposed two facilities – one in Oxford, with Oxford Biomedica, and the other one in Cobra Biologics in Keele and they have been manufacturing AstraZeneca vaccine for some months now. And it’s being finished in a company called Wockhart in North Wales,” [...] said Ian McCubbin, manufacturing lead for the Vaccine Taskforce.


Pfizer manufacture: Through its existing mRNA production sites in Mainz and Idar-Oberstein, Germany, BioNTech is able to produce mRNA for commercial supply after having already produced the vaccine candidate doses for the clinical trials. BioNTech will also increase its manufacturing capacity in 2021, once a third site in Germany will start manufacturing to provide further capacities for a global supply of the potential vaccine. Critical to distribution in the U.K. will be Pfizer’s manufacturing site in Puurs, Belgium, one of Pfizer’s largest sterile injectable sites. The Puurs site is being used primarily for European supply but will also serve as back up supply to Kalamazoo, Michigan, for the U.S. market. source.


The priority list for who is to be vaccinated is here, in quite a bit of detail.

1. residents in a care home for older adults and their carers

2. all those 80 years of age and over and frontline health and social care workers

3. all those 75 years of age and over

4. all those 70 years of age and over and clinically extremely vulnerable individuals[footnote 1]

5. all those 65 years of age and over

6. all individuals aged 16 years [footnote 2] to 64 years with underlying health conditions which put them at higher risk of serious disease and mortality[footnote 3]

7. all those 60 years of age and over

8. all those 55 years of age and over

9. all those 50 years of age and over


 Related Pages:  (faulty links updated 20201202)

Essay 291 - Effects of an outbreak  what it says, effects, but some description of what we have (and not)

Essay 293 - Covid-19 charts  charts published daily reflecting concerns and issues.

Essay 295 Long-term Distancing

Coronavirus (Y10+)   modelling problems

Epidemics                  more general theory

Infectious disease      looking at the 2020 problem, particularly effects of the reproduction number changing.

Essay 298 Covid Consequences       Surprisingly prescient, considering when it was written.

Essay 299  Covid in April

Essay 300  Covid in May

Essay 303 Covid in June

Essay 304 Covid Disparities              A report on the report, including what it doesn't say.

Essay 305  Risk

Essay 306 Covid in July

Essay 311 Covid in August                 International charts updated

Essay 316 Covid in September          European comparison charts updated

Viruses are very small                        Worth reading, I think. (But I would, wouldn't I?)

Essay 317 Covid vs Influenza   

Essay 318 Covid in October                Charts updated through November

Essay 322 Covid in November            UK Regional chart and table through Lockdown Two

Essay 325 Covid in December            Updated graphs of rate and prevalence, plus US charts.

Essay 328 Vaccine progress               This very page

Essay 332 Covid inJanuary                 Maunderings through the month, very bored.

  Email: David@Scoins.net      © David Scoins 2020