Announcement

Collapse
No announcement yet.

COVID (SARS-CoV-2) - Preliminary thoughts. JJackson personal opinion.

Collapse
X
 
  • Filter
  • Time
  • Show
Clear All
new posts

  • #16
    I like graphs so I have made a simple sheet
    Click image for larger version  Name:	table.JPG Views:	0 Size:	40.1 KB ID:	833034
    and the graph from it. It looks at a period of about a week showing the change in case numbers for those countries with over 100 cases.
    The blue bars (and y axis scale) show the new cases over that time and the orange show those cases divided by the area's populations (the y axis scale is correct if read as per 50 million people). So, relative to their populations, new cases are high in S Korea, Hubei, Italy and Iran and low in China as a country and the other listed countries. I did have China (excl. Hubei) but removed it as the orange bar was too small to see.
    Click image for larger version  Name:	graph.JPG Views:	0 Size:	56.8 KB ID:	833035

    Comment


    • #17
      SouthKorea-Daegu : 73,75,109,130,168,87,168,80,111
      almost under control outside Daegu ; like China ex Wuhan
      that looks to me as if it can be contained with "war against the virus (Mar02)"
      and no, South Korea is not communist,one party, draconian,lying etc.
      [what all had been said when cases in
      China started to decline ]
      WHO speaks of 5 clusters in South Korea but no community spread,
      so they think it can still be contained
      https://www.who.int/dg/speeches/deta...--2-march-2020

      Soth Korea-Daegu-Gyeongbuk daily new cases (135),34,32,56,57,93,36,64,19,22
      Last edited by gsgs; March 4, 2020, 11:14 PM.
      I'm interested in expert panflu damage estimates
      my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

      Comment


      • #18
        South Korea-Daegu-Gyeongbuk daily new cases (135),34,32,56,57,93,36,64,19,22,29,35,27,~20?
        seems to be going down in South Korea , even in Daegu

        I'm interested in expert panflu damage estimates
        my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

        Comment


        • #19
          The aim in this post is to re visit a concept introduced in the H7N9 discussion thread some years ago that I think of as the Zoonotic Edge (it probably has an accepted name but I do not know it).
          Viruses, and RNA viruses in particular, mutate rapidly and on entering a new host infect millions of cells before spreading to the next host. The consequence being that they operate as a quasi-species with a range of genetic diversity within one host that looks very like the range across samples from multiple hosts in a sampled population. If a sequence is sampled and published it shows the most common nucleotide (NT) found at each position along the sequence. This is a simplified picture as some of these positions may have high proportions of other NTs (if it is 49% A & 51% G it will show G as the NT). When a new infection occurs the new host will get a starting viral load, including whatever mix happened to be in the droplet, and will then start its own quasi-species. Flu has no error checking when assembling a new virion, COVID has one level as its RNA strand is 30,000 NTs long and consequently fragile (flu’s strands are about 1500 NTs). Humans have 11 levels (from memory). In PCR tests an equivalent DNA strand is created from the RNA as the double helix makes it more stable.

          The zoonotic edge is two way and we see this with human flu from farmers getting in to their pigs and swine flus getting into the farmers. COVID’s greatly increased geographic spread with it new human vector will put it in contact with new, and possibly susceptible, species which may create new constellations with their own adaptions leading to new reservoirs from which zoonotic emergence into us can occur. This came up in the current TWiV which I will add to the links below.
          Another TWiV topic that I do not think I have written about, as it was not relevant to flu regards CoV evolution in humans. I had thought about this some years ago as it came up in a previous TWiV interview with Stanley Perlman regarding MERS in Camels. He thought that young camels had very mild disease, as children do with SARS-2, and that the high prevalence of disease in the adult population meant all young camels caught it. When they were older and challenged for a second time they get much milder symptoms, although without that childhood exposure might have got seriously ill. The virologist being interviewed in the latest TWiV brought this back to mind as he said he thought that our common cold causing CoVs probably emerged long ago, before we had records, and could have been just as big a problem, for the humans at the time, as MERS, SARS-1 and SARS-2 have for us. Again postulating CoVs generally are mild in children, and upon reinfection, then once a generation of children have had mild disease it will become mild for life and the same pattern would be repeated each generation. This would lead to the only people at high risk of severe disease from OC43 etc. would be older people who had never had a cold in their life (there were accounts of severe illness in remote Amazonian tribes attributed to colds or flu but no data on the exact causative agent). If COVID does follow the same path then it may become endemic and after a few generations become another common cold strain. What I had not known is there are 4 common cold CoVs in two groups of two, each member of these groups are genetically very similar but do not provide protective immunity to their close relative, and that this is likely to be a common CoV trait so if SARS-2 does provide immunity to re-infection it probably will not for a closely related SARS-3.

          [Edit] What I forgot to mention, but came up in both the TWiVs, was antibody decay. MERS antibodies can fall to undetectable levels, in humans, in two years. I do not remember anything on SARS-1 and it is obviously too early to say anything about SARS-2.

          Links:
          This is to the Zoonotic Edge post which tries to explain it in terms of set theory using Venn diagrams. It is a long thread and the relevant posts are #72 and 79. https://flutrackers.com/forum/forum/...4-closed/page5

          This is to my reply to one of Mike Coston’s posts explaining another made up term ‘jumpers’ which relates to the very rare occurrence when a virus jumps from one host to the next, almost all generations and replication takes place in one host. https://flutrackers.com/forum/forum/...les#post778768

          This is to the current TWiV which I give a 'highly recommended'. I do not have a link to the Perlman one and cannot even remember how long ago it was - post SARS-1 and MERS but pre SARS-2.
          TWiV 591 http://www.microbe.tv/twiv/
          Last edited by JJackson; April 16, 2020, 11:33 AM.

          Comment


          • #20
            Quo Vadimus - There must be some kind of way out of here (said the joker to the thief).

            This pandemic is about to enter a new phase for many of us and I think a look ahead is warranted.

            Many western countries are reaching a peak in their cases as their shutdown measures have worked through the system and now need to shift focus to getting their economies functioning again without a major resurgence of cases. There is bound to be enormous pressure to ease curbs and much talk of the wave having passed. I do not think this is the case the wave has moved to new areas but the underlying fundamentals have not changed. We do not have enough PCR test capacity for wide spread community testing nor do we have any reliable serology tests in volume. Sadly I have not seen evidence of the lockdown time being used to setup and train contact tracing teams or national online self-reporting systems, for those who think they have been infected but recovered at home. In short we do not know a great deal more about the overall situation in our countries than we did at the beginning of the shutdown.

            How many people have been infected? Without serology testing we have no idea, we all hope there have been many asymptomatic cases but I doubt that. I think most of the reported cases were technically pre-symptomatic at the time of testing. My guess is there have been very few truly asymptomatic cases a better question is how many mild cases have there been, which is where the collection of self-reported mild case data is needed, so when rapid test kits are available these people can be cleared to return to work.

            Will this follow a wave structure like the flu pandemics? I see no reason why it should. We have caused a wave shape by the lockdown measures but this is entirely artificial. Flu’s waves were due to its extreme seasonality and the herd immunity neither of which apply. For COVID I am working on the assumption that there have been about 20 million cases globally which is only 0.25% infected to-date and nowhere close to enough to cause any slowing in the rate of spread. We have learnt a lot about social distancing and hand washing but will need to restructure the way we work, and travel to work by public transport in urban areas, to stop numbers exploding again. I see no way of opening leisure activities like restaurants, cinemas, sporting or religious gatherings possibly for a year or more.

            What is going on with testing? PCR test capacity is increasing everywhere and this needs to continue but the promised rapid test kits for IgM and IgG have largely failed to deliver due to very poor reliability, much of which can be put down to lack of specificity, so the other common human corona viruses, which cause colds, are also reacting. These will get sorted out but the delay is going to make relaxation of lockdowns much more difficult. Had they worked they could be used to clear those infected but not PCR tested to restart the economy and free up PCR capacity for early diagnosis which is where they are of most use.

            Where is the big danger now? The Indian sub-continent & Africa. Between them they account for about 3 billion of the world’s 7.8 billion population and have no way of managing the levels of infection seen in any of the countries effected to-date. They have neither the medical capacity nor the economic capacity to handle a lockdown. Their only saving grace is their youth skewed population demographics. The CFR as SARS-2 rips through their populations unchecked is truly scary I fear 10% could be a low estimate. The graph below is from the current WHO sit-rep and the hardly visible blue and green sections account for more than twice as many people as the yellow and red. Will the reds and yellows help out the blues and greens in any meaningful way given their own problems? This seems unlikely.


            Click image for larger version  Name:	WHO graph.JPG Views:	207 Size:	136.7 KB ID:	850137

            I have made a start on a more technical post looking at the vaccine, therapeutic prospects and disease dynamics which I will add when completed.
            Last edited by JJackson; August 19, 2020, 08:41 AM.

            Comment


            • #21
              SARS-2/COVID
              I have no background in anything I am going to write about here so please take the following as a guide only and NOT medical advice. My aim is to provide some background only.

              Disease progression.
              Broadly from infection (day 0) to obvious symptom onset (day 0-7) mild to moderate (at home 7-14) hospitalisation and passive oxygen support (14-21) ICU mechanical ventilation (21-30). Obviously for most the immune system gets control at some point and this progression reverses direction. On this time line the peak viral shedding seems to ramp up from day 5, peaks around 10 with a longer tail but there is not much viral load by the time of ICU admission. The antibody response timing is IgM starts to build from day 10 (day 4 post symptom onset for detectable load) gradually being replaced by IgG which should test positive 4 or 5 days after the IgM. A week after IgG detection levels should be good enough to prevent reinfection.
              The receptor binding domain (RBD) is found on the tip of the spike protein which binds to the ACE2 receptor on the host cell surface. This may not be the only receptor the virus can use to gain entry but is thought to be the primary route used. Once infected the cell will produce interferons, which attract immune cells, and viral RNA and proteins will be recognised as foreign and exported to the cell surface. The cell will also undergo apoptosis (commit suicide) and spill its contents into the surroundings. Dendritic cells (DC) will collect the fragments released and transport them to the lymph nodes where they are transported to MHC proteins on the DC’s surface and displayed to B cells resident in the lymph node which determines if they are ‘self’ or foreign. If not-self the B-cells will start to produce IgM antibodies which are a first approximations of a targeted response. This is a change from an Innate response to an Adaptive immune response targeting a specific pathogen. Each B-cell is producing a response specific to the pathogen fragment that the DC presented to it. If the B-cell is repeatedly presented with the same fragment it will change to a plasma B-cell which is capable of producing vast amounts of antigen. The IgM has a number of binding sites none of which are very specific so they do not bind with high affinity but their combined effect produces reasonable avidity (the combined effect of lots of fairly low affinity bonds). The adaptive response improves the specificity over time and begins to produce IgG which has a single binding site but is a much better match so has high affinity (one strong hook rather than lots of weak ones).
              These antibodies will be made to the different viral fragments presented to individual B-cells which will enhance the immune response but only those that bind to the RBD produce Neutralising immunity. All the antibodies (Abs) enhance the immune response but only neutralising antibodies (NAbs) prevent infection as they bind to the RBD and prevent attachment of the spike protein to the ACE2 receptor. Sterilising immunity is achieved when a host has circulating NAbs that results in protection from subsequent infection without causing any noticeable disease.
              This is a very basic overview and I will look at some aspects in more detail later.

              Click image for larger version  Name:	dendrictic.JPG Views:	129 Size:	106.9 KB ID:	850508
              Click image for larger version  Name:	igm igg.JPG Views:	113 Size:	12.8 KB ID:	850509

              Testing
              RT PCR testing takes RNA from a swab, makes a DNA equivalent and then repeatedly amplifies it a number of cycles until there is sufficient product to react with a probe giving a fluorescence bright enough to be detected. The number of amplification cycles needed to get this reaction is counted and a threshold is selected. Typically if there is plenty of viral RNA in the sample 25 cycles may be required, if 35 cycles has failed to reach the diagnostic threshold the test would be deemed negative (these numbers are typical but will vary by test protocols). Serology testing may be by ELISA which is quantitatively measuring levels of IgM and IgG or by rapid anti-body tests which have been in the news as many have not worked reliably. Normally these would be rigorously tested to make sure they produced positives only for the desired Abs but due to the rush manufacturers have been allowed to bring tests to market without the usual verification requirements. If they are not specific enough they will show a false positive due to cross reactivity with the spike proteins from common cold corona viruses or false negatives if they are not sensitive enough to pick up low levels of Abs. In theory they are fairly simple in a drop of blood is placed on an absorbent wick and as it moves along it is reacted with an IgM test then IgG and finally a control that reacts with blood to show it reached all the way to the end. As with a pregnancy test a line will appear, or not, for each reaction. As the IgM is not very specific it is prone to cross reactivity. If the test works an IgM positive is an indication of recent infection, IgG positive should mean a robust immunity to reinfection and the host would be safe to leave self-isolation.
              PCR positive does not necessarily mean that there is infectious virus only that there is viral RNA present which could just be viral RNA fragments and is probably why the recorded ‘reinfections’ are not real but due to the first test falling below the sensitivity threshold with a subsequent, better swab sample, reaching the threshold. Attempts to grow virus two weeks after symptom start usually fail although, clinically, the patient is getting worse.
              As this post is already quite long I will break here and return with a part II in which I will look at COVID disease progression and the many other immune cells and signalling chemicals and some of the cell pathways involved in attacking the virus and routes for invoking those responses.

              The two graphics are taken form Vincent Racaniello's Virology lectures. The first covers the innate system and the second the adaptive
              https://www.youtube.com/watch?v=F9TClYS_Ch0
              https://www.youtube.com/watch?v=28gIJ2rrN7I
              Last edited by JJackson; August 19, 2020, 08:44 AM.

              Comment


              • #22
                pr?alable :

                "Donc, pour r?capituler, la Chine a r?ussi ? ramasser le premier cas, sur un fond d'environ 150 cas de pneumonie acquis par la communaut? par jour ? Wuhan, trouver la source des clusters, l'identifier comme COV, le s?quencer et signaler tout cela au monde via l'OMS dans deux semaines et avant qu'aucun cas ne se soit pr?sent? hors de Chine. Rien de tel n'a jamais ?t? fait auparavant et si vous regardez en arri?re l'?pid?mie de H1N1 (2009), les ?tats-Unis et le Mexique ont ?t? beaucoup plus lents ? comprendre ce qui se passait, avec un r?seau de surveillance des maladies et de la grippe bien mieux compris."
                Si je partage le fait qu'ils ont fait un exploit, pas acc?s connu de bien du monde, ceci me semble r?v?ler que la d?marche ?pid?miologique seule n'est pas toujours explicative.
                Nous parlons de lieu de commerce, mis ? l'index, depuis un bon moment, mais culturellement important.
                Nous parlons de populations humaines na?ves en pas grand chose qui ont du recevoir, notamment un paquet de x types vaccins influenza et autres et qui usent et abusent de m?decine traditionnelle ou pas ...

                Si du sang ( etc) des premiers patients, au d?but de la maladie, existaient, on pourrait apprendre quoi de l'?tat de leur syst?me immunitaire en d?but de maladie ?
                Je veut juste sugg?rer qu'il y a du avoir x prodomes pas identifi?s ? ce stade, ? la fois chez les humains et les animaux ... Et comme ils veulent ce genre de lieu, ce que je respecte, je pense que ce qui doit ?tre fait, c'est les aider ? faire ?merger ce qui sera ?clairant.






                Comment


                • #23
                  Probably my poor French but if I understand you you are asking about what could be learnt from the blood from patients collected early in the disease outbreak. Not much apart from how early in the disease progression the blood was drawn, based on the IgM/IgG ratio. The Chinese tradition of live animal markets is always going to be a problem for zoonotic disease emergence as it is going to put the public in direct contact with microbial pathogens living in the animals they eat. This is not solely a Chinese problem but is prevalent in many societies that have only recently industrialised due to not having had access to refrigeration and cold chain storage. In the west we have had the means of keeping animal food products safe from spoilage for long enough for us to change to a centralised slaughter and refrigerated transport system so this has become the cultural norm. For much of the developing world this is not an option, for China it is now an option but cultural change takes time.
                  I am not clear on your question relating to the use of TCM which is going to make direct comparison with Chinese and western COVID patients very difficult as nearly all of the Chinese cases had some TCM incorporated in their treatments. There are now a number of structured clinically controlled trials of the TCM treatments used, as there are for the western pharmaceuticals, however none of these have yet produced any results (except for a small number of trials with a statistically insignificant number of patients). Many of the TCMs are used to reduce temperature, inflammation etc. and may well turn out to be useful but I have no idea which will have helped and which do harm, or had no effect, but the same is true for all of the off label drugs being tried in the west.

                  Comment


                  • #24
                    oui, c'est exactement cela. Comme, il y a du y avoir des pr?l?vements et pas que de sang, il doit exister bien du mat?riel. Je veut sugg?rer que ce ne doit pas ?tre des populations humaines et animales na?ves . Il a ?t? ?crit que l'origine ?tait en dehors du march? et multi-centrique. Ils ont donc identifi?, ? ma connaissance, le premier foyer, mais je trouve que le contexte d'?mergence n'a pas fait l'objet d'une description suffisante, ni au niveau des humains ni des animaux. Ce milieu animal et humains non na?f, ce ne serait pas un lieu de s?lection ideal pour permettre une vraie ?mergence ?

                    Ils ont et font un boulot magnifique, sur leur m?decine traditionnelle, m?me si certains produits sont tr?s surprenant, exemple :
                    https://dailygeekshow.com/totoaba-vi...elle-chinoise/

                    Une derni?re remarque: ils avaient deux labos en local et ne faisaient que des pr?l?vements dans des grottes ? bien des kilom?tres ? Mais ils ont eu et aurons le droit de communiquer, vu le contexte actuel ?

                    Comment


                    • #25
                      I have no evidence but my guess would be that the market was not the source just the first cluster large enough to be picked up against the background of community acquired pneumonia cases. There have only been about 20 single point nucleotide changes since the first sequence which is very slow compared to flu sequences, which I am more used to looking at. This puts a limit on how far back the original zoonotic jump was, at least how far back all of the human cases that have ever been sequenced could have originated. This limit is about 6 months. Something could have been circulating inefficiently in humans before then and then acquired a key mutation allowing for efficient h2h causing the explosion of cases. Alternatively a human optimised form may have occured in an animal and then made the jump to us, without finding an earlier sequence we can not know. There are so few sequences from wild animals there could be enormous reservoirs of virus in some species we know nothing about.

                      Comment


                      • #26
                        Les f?tes justifient des achats provenant souvent m?me plus de six mois de travail. Seuls ceux qui connaissent l'histoire de ce march?, des produits et des communaut?s qui les alimentent, peuvent faire. Cela se d?nomme une enqu?te de terrain, en vue d'affiner ce que l'enqu?te ?pid?miologique a sugg?r? ... Il existe, peut ?tre, des brigades d'enqu?te v?t?rinaire et ou mixte, en Chine, pour cela, ou pas encore ?

                        Comment


                        • #27
                          Merci, j'ai retrouv? ceci :

                          Le coronavirus du SRAS (SARS-CoV), l'agent causal de la grande ?pid?mie de SRAS en 2003, provient des chauves-souris. De nombreux coronavirus de type SRAS (SL-CoV) ont ?t? d?tect?s chez les chauves-souris, en particulier ceux qui r?sident en Chine, en Europe et en Afrique. Pour mieux comprendre la relation ?volutive entre le SRAS-CoV et ses r?servoirs,
                          334 chauves-souris ont ?t? collect?es dans la ville de Zhoushan, province du Zhejiang, Chine, entre 2015 et 2017.
                          L'amplification par PCR de la prot?ine coronavirale conserv?e RdRp a d?tect? des coronavirus dans 26,65% des chauves-souris appartenant ? cette r?gion, et ce nombre a ?t? influenc? par les changements saisonniers. Des analyses g?nomiques compl?tes des deux nouveaux SL-CoV de Zhoushan (ZXC21 et ZC45) ont montr? que leurs g?nomes avaient respectivement 29 732 nucl?otides (nt) et 29 802 nt de longueur, avec 13 cadres de lecture ouverts (ORF). Ces r?sultats ont r?v?l? 81% d'identit? nucl?otidique partag?e avec les CoV du SRAS humain / civette, ce qui ?tait plus ?loign? que celui observ? pr?c?demment pour les SL-CoV de chauve-souris en Chine. Surtout, en utilisant des tests pathog?nes,
                          nous avons constat? que le virus peut se reproduire et provoquer des maladies chez les rats allaitants
                          et d'autres ?tudes ont montr? que les particules de type virus peuvent ?tre observ?es dans le cerveau de rats allaitants par microscopie ?lectronique. Ainsi, cette ?tude a am?lior? notre compr?hension de la diversit? g?n?tique des SL-CoV port?s par les chauves-souris et a ?galement fourni
                          une nouvelle perspective pour ?tudier la possibilit? de transmission inter-esp?ces de SL-CoV en utilisant des rats allaitants comme mod?le animal.


                          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135831/

                          on y trouve ceci:

                          Suckling rat infecting assay

                          To test the pathogenicity of the ZC45 agent, infection experiments were performed in suckling rats. 3-day-old suckling BALB/c rats (SLAC, China) were intracerebrally inoculated with 20 μl of volume grinding supernatant of ZC45 intestinal tissue. Animal housing care and all animal experiments were performed in a biosafety level 3 (BSL-3) facility and were approved by the local ethics committee. After 14 days, the brain, lungs, intestine, and liver tissues from infected rats were selected to prepare pathological sections. Briefly, the tissues were fixed in 10% (vol/vol) neutral-buffered formalin. After routine tissue processing, including dehydration by graded alcohol solutions, washing, and incubation in paraffin, 4 ?m thick sections were cut and stained with hematoxylin and eosin (H&E). Approximately 2 h later, the prepared tissue sections were imaged using optical microscopy (Olympus, Japan).

                          https://en.wikipedia.org/wiki/BALB/c


                          je me demande si la contamination de rattons tr?s jeunes par l'ambiance, ne peut pas ?tre l'?quivalent d'un inoculation intrac?r?bralle.

                          Je sais que la maitrise des rongeurs dans les ?levages et les commerce ( sauf au Vietnam) est demand?e, mais dans certains lieux notamment de commerce multi-esp?ces avec des carnivores, ou les rats sont, pr?sent, ?lev?s ou r?cup?r?s pour nourrir certains sujets, cela n'est pas advenu ?

                          Pour ?tre intervenu, chez des grossistes de n?goce d'animaux, ? Paris, le principe ?tait de r?cup?rer, les invendus des ?levages de rattons d?stin?s aux unit?s de recherche m?dicales...

                          Ma question devient :

                          si la contamination intrac?r?brale est efficente, comment mimer cette forme de contamination par des conditions de d?tention particuli?re ?




                          une remarque: si ce sont des animaux ?lev?s pour les usages en laboratoire, ce sont pour certains des animaux de compagnie ...

                          Comment


                          • #28
                            Pour ?tre tr?s clair,

                            si certains ?voquent que cela a pu se passer dans un des deux labos, il me semble plus probable que cela se soit produit en dehors, mais ? cause de r?gles d'un autre temps, mais pas qu'en Chine ...


                            Que les scientifiques, ici ou l?, veuillent user ou abuser, de lign?es animales "tar?es", ? souhait, celle cit?e, am?ricaine, n'en est qu'une, il me semble temps que ces lign?es restent, strictement, dans leur labo.
                            https://en.wikipedia.org/wiki/BALB/c

                            Car, quand on les met ou produit, dehors sans vraie protection et gestion, pour des motifs rarement honorable, voir dossier glyphosate, ou celui-ci, des lign?es tar?es et na?ves, cela a pu faire , fait et fera des bombes potentielles... Pour imposer cela, donc l'?mergence de vraies r?gles et pas qu'en Chine, il faut d?montrer ce risque, ce que les chinois, mais pas qu'eux, peuvent d?sormais faire...

                            Alors Messieurs et Mesdames, les am?ricains et chinois, mais pas que, faites nous un peu grandir ...
                            Que l'on arr?te, enfin, de mal parler de la faune sauvage
                            Que ceux qui veulent en user se donnent les moyens de prouver le non risque de leurs pratiques
                            Que les mondes des laboratoires se mettent enfin ? niveau ...


                            J'ai pass? bien du temps sur la notion de race animale, que je respecte et d?fend, quand elle a du sens, mais ce que je voie dans le cadre de l'?levage des animaux dit domestique ( un terme p?joratif quand on use de son cerveau ) de chien et de chat, me semble aussi affligeant de ce que je sais des producteurs et utilisateurs des animaux de laboratoire ...

                            Messieurs les g?n?ticiens, chinois et autres, montrez nous comment le m?nage n?cessaire, du ? la science, peut enfin se mettre en oeuvre, par ce que le co?t des b?tises ( pour ?tre courtois) , cela fait vraiment beaucoup trop ...

                            Comment


                            • #29
                              On vaccines
                              With 200+ SARS-CoV-2 vaccines in development and several in some version of a phase 3 trial this post aims to look at the process, the technologies and the problems.

                              Under normal circumstances bringing a vaccine to market would involve lab work, animal trials and 3 levels of clinical trials.
                              Phase 1 would include about 20 healthy young adults looking for obvious side effects.
                              Phase 2 would occur (assuming no problems in phase 1) with about 100 subjects with slightly increased age ranges and would again be looking for contraindications but also for the development of antibodies and a T cell response.
                              Phase 3 (again assuming a good outcome in phase 2) would include 10s of thousands of participants some of which may be in higher risk groups looking for the immune response and less common adverse reactions.

                              These are not normal circumstances and the usual rules have not been applied with phase 1&2 being rolled into one trial and phase 3 results not being waited for and analysed before wider distribution of the vaccine. There are dangers involved in this some of which I will expand on.
                              In the phase 3 trials the first data to become available will be efficacy and once we have a couple of hundred subjects that have been infected in the placebo arm of the trial it should be fairly clear how effective the vaccine has been based on how many cases there have been in the vaccinated cohort, and how severe the disease has been. If this looks promising then there will be immense pressure to start rolling out the vaccine which has already been manufactured and is ready for deployment. What we will not know is how safe it is or how long lasting. Guillian-Barre syndrome is a known rare side effect of vaccines but only occurs in about 1 in 100,000 cases so probably would not be detected in a 30,000 person trial even if it was allowed to run its full course. Other more common reactions may be picked up only late in the trial but if serious and occurring in 1 in 10,000 would probably only be found after careful examination of a completed trial, particularly if it is slow to develop, but in 300 million would equate to 3000 cases. It may still be worth deploying the vaccine, on balance, but it would be useful to know before deployment as it could be disastrous for vaccine uptake generally with many very safe and effective vaccines already suffering at the hands of the anti-vaxers.

                              The next problem is the level of protection the vaccine provides and how long it lasts. There were 6 previous zoonotic CoV emergences, the 4 common cold CoVs plus SARS and MERS. We are being continually reinfected by the cold viruses with a periodic boost to antibody levels giving mild, or no, clinical disease. SARS-1 had a 10% CFR and MERS is about 30% (SARS-2 crude CFR is about 4%. Cristian Drosten estimates SARS-2 IFR as 0.8% compared to 0.05% for seasonal flu) but as SARS-1 was eradicated and MERS cases are too few to find reinfections we can study anti-body decay over time. Both follow the standard fast decline over the first 3 months, as most of the B-cells produced to fight the infection die off. A slower decline then takes place as the longer lasting memory cells persist and provide some circulating antibodies but, without any virus, just tickover ready for reactivation. After 2 years levels are very low and after ten undetectable.

                              This brings me to another novel aspect of the current situation. Normally there would be only one vaccine being brought to market, not several all competing to be first, and this time there are many novel approaches to vaccine design including some of the leading candidates using platforms that have not been licensed before. We have no idea what effect it is going to have if an early candidate looks promising but a latter product is much better. What effect would getting a shot of the second be if you had already had the first to market? It could cause a boost or it could react badly we have never had to test if previous vaccination could be a co-morbidity or could invoke ADE.
                              Last edited by JJackson; October 12, 2020, 02:13 PM.

                              Comment


                              • #30
                                The issue of herd immunity has come up in the discussion thread and Bertrand raised it in the immunity thread in this workshop. So it is probably worth revisiting.

                                In theory it is fairly straight forward and obeys the formula 1- R0-1 where R0 is the natural reproductive number i.e. the number of people 1 average person infects. So if the R0 is 3 then it is one minus one third or about 66%. The Rt is the actual reproductive number after all the physical distancing, hand washing and mask wearing are taken into account and is much easier to calculate as the current slope of the new cases curve will give you a good approximation. At the moment it is going down fairly steeply so the Rt is well under one. Wikipedia gives the R0 as 3 to 4.

                                That’s the theory bit but the practice is more complicated. The calculation works very well if the virus in question can be vaccinated against and gives lifelong sterilising immunity. At the moment we do not know how sterilising or long lasting protection after SARS-CoV-2 infection, or vaccination, are. It does seem to generate fairly high anti-body titers and a good B & T cell response however reinfections can occur. The concept of sterilising immunity, or for that matter immunity, is not clear cut. Immunity from what? Illness or infection if illness what level of symptoms? If infection how are you measuring that? Even the vaccines that are meant to give sterilising immunity don’t actually mean you do not get any cells infected, just that the virus never establish a foothold, but you could still be technically PCR positive. The herd immunity concept could also be applied to the virus for each cell infected it has to maintain at least one new cell or it will die out. As long as it never gets to a level where it infects anyone else, or causes any symptoms, we would view that as sterilising immunity.

                                The vaccines for COVID give % effectiveness figures but these are for symptomatic illness not infection. The other problem is there has not been enough time to find out how quickly the antibodies will decay or the concentrations at which they start allowing more serious clinical disease. The early B & T cell response also looks excellent but again there has not been time to see how well they cope with reinfection once the antibodies have returned to baseline.

                                The immune system has generated these cells, and lots of antibodies, against the acute phase of the disease but once the disease is cleared the antibodies have a half-life which will be of the order of a month. Most of the effector cells that produced them will also die off leaving a small number of memory B cells making a few SARS-2 specific antibodies and few memory T-cells that can kill off any infected cells. How many antibodies can those B cells make if there is no antigen to keep them activated and is this enough to prevent infection? How quickly can they proliferate if the virus does reappear? We may need to wait a few years to get an answer. Without knowing the answer to these questions we do not know if herd immunity is achievable and if it is in one area can it be made global? We still have diseases like Polio and still need to immunise against them in the West despite it having been eradicated here years ago.

                                The last part of this post is going to be guess work based on my understanding of the situation.

                                I think the level of antibodies and CD8 T cells generated by both infection and vaccination are likely to be so high initially (in most people, but the responses have been very variable so please assume everything in this post is for an average response) it will provide protection against moderate disease and keep any virus at such low levels they are unlikely to infect anyone else. As time passes and levels drop the probability of passing infection on will start to climb slowly and the asymptomatic carriers will start to be a problem. The level of clinical severity will also begin to creep up. How quickly all this will happen is one of the unanswered questions above. I don’t think there is a realistic chance of eradicating this disease, as was done for SARS-1, so I see two possible scenarios. Either we go down the flu route with repeated vaccinations at some regular interval, yet to be determined, or we hope SARS-2 follows the seasonal cold CoVs and gives mild disease in children and then circulates so widely you get booster shots regularly enough to very rarely get more than mild disease. This also seems to be the case with MERS in camels.

                                Crystal ball gazing is notoriously unreliable so this is just one view in many. I know there are a number of links in the discussion thread, and I have not read any of them, but I suspect they are drawing their conclusions from the same data I am. They may well be interpreting it differently.

                                There is more detail on the immunological aspect of all this in the COVID - Immunity thread.

                                https://flutrackers.com/forum/forum/...id-19-immunity
                                Last edited by JJackson; February 21, 2021, 04:47 AM.

                                Comment

                                Working...
                                X