EUA for Plasma, Vaccines, B-cells and IFN-β1a; COVID-19 Science News
Summary
- EUA for convalescent plasma on questionable grounds
- SinoPharm inactivated virus vaccine raises neutralising IgG
- Pfizer/BioNTech new candidate shows fewer side-effects
- Neutralising antibodies probably protect against reinfection
- B-cells detected in recovered patients 3 months after recovery
- Inhaled IFN-β1a shows promising preliminary results
- Ebola outbreak in DRC growing
In The News
The US FDA has granted Emergency Use Authorisation (EUA) to convalescent plasma for use in patients with COVID-19. [1]
Examining the submitted request for EUA to the FDA makes this decision somewhat questionable.
By far the most egregious part of the request is that there is no control group! [2,3]
The EUA request sets a limit IgG plasma >12 (S/Co) (which is not justified through experiment or reference to another piece of work) for the amount of antibody given to patients above which they claim a significant effect on mortality. However, their preprint divides the antibodies levels into three different levels: > 18.45, 18.45 > x > 4.62 and < 4.62. This is a bit odd, since the latter way of representing the data actually presents a more convincing case for the treatment, as it shows a dose-response in every group tested, albeit with a different magnitude and despite not meeting statistical significance in some of the correlations. This latter point is likely why the cutoff was changed and if it the case raises major red flags, as it is not sound science.
Another curious passage:
“Notably, the vast majority of the thromboembolic or thrombotic events (n=55) and cardiac events (n=562) were judged to be unrelated to the convalescent plasma transfusion per se.”
This would be fine in the presence of a control group which would show that these events occurred regardless of plasma. However, again, no justification nor citation is provided. It is completely possible (and if fact probably the case) that the assessment is indeed correct, but the bar for evidence for approval (even if just EUA) should be much higher.
The press conference claiming “35 % reduction in mortality” is utterly false and unsupported by data. [4]
As noted in the request, only two controlled trials have been conducted so far for this treatment. The first (Netherlands) was discontinued due to patients having high levels of antibodies before receiving treatment. The second (China) was in patients with severe COVID-19 (based on what we know these probably would not benefit from receiving IgG antibodies or plasma) and was terminated early due to lack of efficacy. [5,6]
Is the EUA warranted? Perhaps! The presented data is weak however and the grandiose claims that accompanied this EUA are simply false. Look no further than the title of the press release from the FDA for confirmation of the motivations behind this rather rushed EUA. [7]
Vaccines
SinoPharm has released the clinical trial data for their inactivated virus vaccine candidate, a result of their combined phase I/II trial effort. [8]
Three doses were administered, which could present a big logistical difficulty down the road. In terms of antibodies, in phase I, patients showed neutralising antibodies after their first shot only in the medium dosage group, but after the second dose, all dosages showed neutralising antibodies.
Phase II was conducted with the medium dosage, with two shots administered. Notably, one patient did not seroconvert. No data on cellular responses are included. Comparisons of the levels of antibodies raised by the patients to convalescent recovered patients were also not made. [9]
The Pfizer/BioNTech collaboration has released a study that justifies their selection of BNT162-b2 over BNT162-b1 as their vaccine candidate moving into later stages of clinical development. [10,11]
Both b1 and b2 raise neutralising antibodies and both outperfom convalescent patients. The main difference, and reason for b2 being selected, is the better tolerance of b2, with fewer systemic events (side-effects) seen, especially in the older patients. Cellular responses were not compared.
The technical differences between the two candidates:
“BNT162b1 encodes a secreted trimerized SARS-CoV-2 receptor-binding domain. BNT162b2 encodes a prefusion stabilized membrane-anchored SARS-CoV-2 full-length spike.”
Antibodies and immunity
A very interesting study from the University of Washington in Seattle examined a fishing boat’s crew for antibodies against SARS-CoV-2 before they departed for a trip. [12]
Three crew-members were found to have neutralising antibodies. An outbreak of COVID-19 occurred while the ship was out at sea. A total of 104 of the 122 people on board contracted SARS-CoV-2, but all three individuals with neutralising antibodies came back negative.
This is the first sign that implies that neutralising antibodies provide some level of immunity towards contracting SARS-CoV-2 a second time.
A different study, also from Seattle, shows some interesting signs in patients who were diagnosed with COVID-19. [13]
Though they observe that antibody levels start to drop in patients over a 3-month period, they observe these patients acquiring memory B-cells (the cells which produce antibodies) in this time. Memory B-cells are an important component of long-lasting immunity after infection (or vaccination).
To provide a short summary of what is now known about immunity:
1) Most patients who recover raise neutralising IgG to some extent
2) People with neutralising IgG are likely protected to some degree
3) Up to 3 months after recovery memory B-cells and IgG are detected
4) Vaccine candidates are raising IgG in patients higher than convalescent
Overall, this would imply that the vaccine development efforts are on a good track.
Therapeutics
Synairgen has released their data for their phase II trial evaluating inhaled IFN-β1a as a potential treatment for COVID-19. [14]
The treatment appears to help even severe patients, which is great news. It also reduced breathlessness which is something that no other treatment has claimed so far. Some of the effects do not meet statistical significance, however they seem to point in the same direction. No dose response data reported here, that would help the case for efficacy a lot.
Non-COVID News
A whole different issue requiring vaccine production is cropping up, with an Ebola outbreak in the DRC continuing. Hopefully it is contained and the area gets the vaccines it desperately needs. [15]
References
- https://bit.ly/2YoCK3R
- https://bit.ly/3j8qz30
- https://bit.ly/31m7ZOS
- https://bit.ly/3grRqFm
- https://bit.ly/3gsAkHz
- https://bit.ly/3gqOJEa
- https://bit.ly/2YuNhu8
- https://bit.ly/2Qocxhu
- https://bit.ly/32qO94a
- https://bit.ly/3b0RMC0
- https://bit.ly/3glhUZe
- https://bit.ly/34tOKVy
- https://bit.ly/2FVYEFf
- https://bit.ly/3jiv637
- https://bit.ly/34vYuPe
