The biology of coronavirus COVID-19 - including research and treatments

Kinetics of antibody responses dictate COVID-19 outcome

https://www.medrxiv.org/content/10.1101/2020.12.18.20248331v1

Summary
Recent studies have provided insights into innate and adaptive immune dynamics in coronavirus disease 2019 (COVID-19). Yet, the exact feature of antibody responses that governs COVID-19 disease outcomes remain unclear. Here, we analysed humoral immune responses in 209 asymptomatic, mild, moderate and severe COVID-19 patients over time to probe the nature of antibody responses in disease severity and mortality. We observed a correlation between anti-Spike (S) IgG levels, length of hospitalization and clinical parameters associated with worse clinical progression. While high anti-S IgG levels correlated with worse disease severity, such correlation was time-dependent. Deceased patients did not have higher overall humoral response than live discharged patients. However, they mounted a robust, yet delayed response, measured by anti-S, anti-RBD IgG, and neutralizing antibody (NAb) levels, compared to survivors. Delayed seroconversion kinetics correlated with impaired viral control in deceased patients. Finally, while sera from 89% of patients displayed some neutralization capacity during their disease course, NAb generation prior to 14 days of disease onset emerged as a key factor for recovery. These data indicate that COVID-19 mortality does not correlate with the cross-sectional antiviral antibody levels per se, but rather with the delayed kinetics of NAb production.
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This paper is about mortality, not Longcovid. The findings have notable impact on the use of monoclonal antibody therapies and suggest that timing of the therapies critical.

The authors offer some speculation as to the reason:

Our study demonstrated that neutralizing antibody responses developed within 14 days of symptom onset correlated with recovery, while those induced at later timepoints appear to lose this protective effect. It is unclear why antibodies generated after this time point are unable to promote viral clearance and recovery in COVID-19 patients. We speculate that the virus might become inaccessible to the antibodies after a certain time point, by establishing infection within immune privileged tissues. Alternatively, disease may be driven by late-onset antibody-mediated immunopathology. For instance, antibodies from severe COVID-19 patients show pro-inflammatory Fc modifications signature, including high levels of afucosylated IgG1 (Abry et al., 2020), which could potentially drive pathologic responses. Consistent with this notion is our finding that anti-S but not anti-RBD antibody levels in COVID-19 patients correlate with disease severity, length of hospital stay, length of intubation and various clinical parameters of disease. In addition, the levels of anti-S IgG, when matched for similar viral load and days from symptom onset, correlated with COVID-19 severity.
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Notably, the level of many cytokines (including Interferons) relative to anti-S IgG levels, were lower in patients who died, compared to those who were discharged. This is yet more evidence to rule out the "cytokine storm" hypothesis.

Although the authors don't mention this, one key hypotheses is the impaired interferon responses (or even antibody mediated inhibition) observed by others:

https://science.sciencemag.org/content/369/6504/718
https://science.sciencemag.org/content/370/6515/eabd4585
https://science.sciencemag.org/content/370/6515/eabd4570
 
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Snow Leopard said:
Kinetics of antibody responses dictate COVID-19 outcome

https://www.medrxiv.org/content/10.1101/2020.12.18.20248331v1



This paper is about mortality, not Longcovid. The findings have notable impact on the use of monoclonal antibody therapies and suggest that timing of the therapies critical.

The authors offer some speculation as to the reason:



Notably, the level of many cytokines (including Interferons) relative to anti-S IgG levels, were lower in patients who died, compared to those who were discharged. This is yet more evidence to rule out the "cytokine storm" hypothesis.

Although the authors don't mention this, one key hypotheses is the impaired interferon responses (or even antibody mediated inhibition) observed by others:

https://science.sciencemag.org/content/369/6504/718
https://science.sciencemag.org/content/370/6515/eabd4585
https://science.sciencemag.org/content/370/6515/eabd4570
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Somebody asked the question of relevance to LC to the primary author:

 
Snow Leopard said:
The study published in The Lancet:
https://www.sciencedirect.com/science/article/pii/S0140673620326611

Note that the pooled data for symptomatic infections was 70·4% (54·8 to 80·6) (95% CI in brackets)

The data for the LD/SD was 90·0% (67·4 to 97·0), for symptomatic infections with an notably small sample size of ~1370 vaccinated and a wide confidence interval.

But also note that the overall efficacy of the LD/SD group was (including those with positive swabs who did not report additional COVID symptoms described as incl) was 58·9% (1·0 to 82·9). Which again, is an extremely wide confidence interval.
Oh and the result for the LD/LD group was a woeful 3·8% (−72·4 to 46·3) group.

I do not find these numbers very confidence inspiring, even when you look at the cherry picked LD/SD result.

I find the dismissal of your queries by the GP quite concerning actually, as it suggests that they have not read, or do not understand the statistics in the manuscript (and the dangers of cherry picking data) and are simply believing the questionable claims in the media that the "half dose then full dose" of the Oxford vaccine is as good as the approved mRNA vaccines.

I'm once again going to plug this paper as a good argument as to why the ChAdOx1 vaccine should be avoided in favour of the mRNA alternatives (at least until other vaccines with high efficacy are approved).
https://www.medrxiv.org/content/10.1101/2020.12.15.20248278v2.full-text
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Watching TV late last night (UK) and the BBC 24 hour news said that the Oxford vaccine would be approved in days!
 
My letter in today’s Observer: https://www.theguardian.com/comment...-latest-coronavirus-lockdown-was-way-too-late

F4D28BB3-DF01-4AC1-960A-D2A40F772809.jpeg

After I submitted the letter I wrote back to request that a word be changed, but it wasn’t. Bonus point to anyone who guesses what the word was. I’m far less knowledgeable about these things than many of you so I will be interested to see if any of you pick it up and consider it to be an error.

I hope this post is allowed as it’s not really political, but I won’t be offended if moderators disagree and delete it.
 
I’m amazed that the Oxford vaccine hasn’t been scrapped given the much better alternatives available. I guess the Covid panic has overridden capacity for rational/critical thought in the medical establishment and govt, if they had any to begin with. The Lancet paper was full of protocol changes and violations, and even at that the results were unimpressive.
 
Sid said:
I’m amazed that the Oxford vaccine hasn’t been scrapped given the much better alternatives available. I guess the Covid panic has overridden capacity for rational/critical thought in the medical establishment and govt, if they had any to begin with. The Lancet paper was full of protocol changes and violations, and even at that the results were unimpressive.
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Follow the money
 
Sid said:
I’m amazed that the Oxford vaccine hasn’t been scrapped given the much better alternatives available. I guess the Covid panic has overridden capacity for rational/critical thought in the medical establishment and govt, if they had any to begin with. The Lancet paper was full of protocol changes and violations, and even at that the results were unimpressive.
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Hilda Bastian was tweeting about this today, she is not impressed either.



From my perspective, ChAdOx1 nCoV-19 is the Reliant Robin of vaccines.
 
Robert 1973 said:
Yes, I asked them to change mutation to variant, but apparently too late.

I wasn’t sure about saying evolve. Is it not correct to say that variants evolve?
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That would make more sense, but still isn't entirely correct. Variants arise from stochastic factors. That isn't evolution. Variants can become predominant due to "evolution" like selection processes, but variants can become predominant for other reasons too (founder effects etc).
 
I think both the original terms are fine.
The variant carries mutations - which cover any random genetic change.Very likely the problem is down to one particular mutation.
Evolution does not have to require selection. Darwin was completely wrong about that. The Galapagos finch radiation need have nothing to do with selection. Evolve is fine.
 
Sid said:
I’m amazed that the Oxford vaccine hasn’t been scrapped given the much better alternatives available. I guess the Covid panic has overridden capacity for rational/critical thought in the medical establishment and govt, if they had any to begin with. The Lancet paper was full of protocol changes and violations, and even at that the results were unimpressive.
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Cost. It's far less expensive to produce than the mRNA alternatives and requires only normal refrigeration. Cold chains are difficult enough to maintain as it is, at this scale it's just too much for places where the infrastructure and logistics chain isn't strong enough. This is crucial for poor countries, who will most likely use this version exclusively. From memory it's about 10x cheaper than the others.
 
rvallee said:
This is crucial for poor countries, who will most likely use this version exclusively. From memory it's about 10x cheaper than the others.
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As well as the issues about transportation and storage, the Oxford/Astra Zeneca group made a commitment to supply it on a non-profit basis to low- and middle-income countries. This will no doubt help to keeps the costs down.

I seem to recall that they're planning to use the large vaccine production capacity in India to distribute it – though I imagine India might want to produce enough to get the most vulnerable parts of its own population covered before it starts shipping doses elsewhere.
 
rvallee said:
Cost. It's far less expensive to produce than the mRNA alternatives and requires only normal refrigeration. Cold chains are difficult enough to maintain as it is, at this scale it's just too much for places where the infrastructure and logistics chain isn't strong enough. This is crucial for poor countries, who will most likely use this version exclusively. From memory it's about 10x cheaper than the others.
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Who cares how cheap it is, if it isn't good enough to achieve any reasonable threshold of herd immunity? There are other cheaper options that will probably have superior efficacy which will become available soon too.

I'm not a big fan of the idea that poor countries only deserve a crap option.
 
Snow Leopard said:
Who cares how cheap it is, if it isn't good enough to achieve any reasonable threshold of herd immunity? There are other cheaper options that will probably have superior efficacy which will become available soon too.

I'm not a big fan of the idea that poor countries only deserve a crap option.
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@Snow Leopard you'll be relieved/reassured ;) to know that:
"He [AstraZeneca chief] added he believes trials will show his firm has achieved a vaccine efficacy equal to Pfizer-BioNTech at 95% and Moderna at 94.5%."
https://www.thejournal.ie/astrazene...1566-Dec2020/?amp=1&__twitter_impression=true

Apparently it's already been distributed to GP practices in the UK!

Is there more data available out there?
 
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