[BostonCard]

https://marlin-prod.literatumonline.com/...326611.pdf

It explains how some individuals came to receive a half-dose for their initial dose:

Two  dosage  groups  were  included  in  COV002:  participants  who  received  a  low  dose  of  the  vaccine  (2·2 × 10¹⁰  viral  particles)  as  their  first  dose  and  were  boosted  with  a  standard  dose  (in  the  LD/SD  group),  and  subse  quent  cohorts  who  were  vaccinated  with  two standard-dose vaccines (SD/SD group). Initial dosing in COV002 was with a batch manufactured at a contract manufacturing    organisation    using    chromatographic    purification. During quality control of this second batch, differences  were  observed  between  the  quantification  methods  (spectrophotometry  and  quantitative  PCR  [qPCR])  prioritised  by  different  manufacturing  sites.  In  consultation with the national regulator (Medicines and Healthcare  products  Regulatory  Agency),  we  selected  a  dose  of  5  ×  10¹⁰  viral  particles  by  spectrophotometer  (2·2 × 10¹⁰  viral  particles  by  qPCR),  in  order  to  be  consistent  with  the  use  of  spectrophotometry  in  the  phase  1  study  (COV001),5  and  to  ensure  the  dose  was  within  a  safe  and  immunogenic  range  according  to  measurements  by  both  methods.  A  lower-than-antici-pated  reactogenicity  profile  was  noted  in  the  trial,  and  unexpected  interference  of  an  excipient  with  the  spec-trophotometry  assay  was  identified.  After  review  and  approval by the regulator, it was concluded that the qPCR (low-dose) reading was more accurate and further doses were adjusted to the standard dose (5 ×  10¹⁰ viral particles) using  a  qPCR  assay.  The  protocol  was  amended  on  June  5,  2020,resulting  in  enrolment  of  two  distinct  groups  with  different  dosing  regimens  with  no  pause  in enrolment (version 6.0; appendix 2 p 330). A suite of assays  has  now  been  developed  for  characterisation  of  concentration  (which  confirmed  the  low  and  standard  dosing),  and  future  batches  are  all  released  with  a  specification  dose  of  3·5–6·5 × 10¹⁰  viral  particles,  and  this was used for the booster doses in the efficacy analysis presented here.

One thing that I had been looking for is how well the vaccine prevents severe disease:

More than 21 days after their first dose, ten participants were  hospitalised  due  to  COVID-19  (defined  as  WHO  clinical  progression  score  ≥4),  two  of  whom  were  assessed  as  having  severe  COVID-19  (WHO  score  ≥6),  including one fatal case. All ten cases were in the control group (table 5).

So, with limited data (only 10 events), it does look like both the standard and low dose vaccines were effective in preventing serious COVID-19.

BC

[BostonCard]

https://marlin-prod.literatumonline.com/...326611.pdf

It explains how some individuals came to receive a half-dose for their initial dose:

Two  dosage  groups  were  included  in  COV002:  participants  who  received  a  low  dose  of  the  vaccine  (2·2 × 10¹⁰  viral  particles)  as  their  first  dose  and  were  boosted  with  a  standard  dose  (in  the  LD/SD  group),  and  subse  quent  cohorts  who  were  vaccinated  with  two standard-dose vaccines (SD/SD group). Initial dosing in COV002 was with a batch manufactured at a contract manufacturing    organisation    using    chromatographic    purification. During quality control of this second batch, differences  were  observed  between  the  quantification  methods  (spectrophotometry  and  quantitative  PCR  [qPCR])  prioritised  by  different  manufacturing  sites.  In  consultation with the national regulator (Medicines and Healthcare  products  Regulatory  Agency),  we  selected  a  dose  of  5  ×  10¹⁰  viral  particles  by  spectrophotometer  (2·2 × 10¹⁰  viral  particles  by  qPCR),  in  order  to  be  consistent  with  the  use  of  spectrophotometry  in  the  phase  1  study  (COV001),5  and  to  ensure  the  dose  was  within  a  safe  and  immunogenic  range  according  to  measurements  by  both  methods.  A  lower-than-antici-pated  reactogenicity  profile  was  noted  in  the  trial,  and  unexpected  interference  of  an  excipient  with  the  spec-trophotometry  assay  was  identified.  After  review  and  approval by the regulator, it was concluded that the qPCR (low-dose) reading was more accurate and further doses were adjusted to the standard dose (5 ×  10¹⁰ viral particles) using  a  qPCR  assay.  The  protocol  was  amended  on  June  5,  2020,resulting  in  enrolment  of  two  distinct  groups  with  different  dosing  regimens  with  no  pause  in enrolment (version 6.0; appendix 2 p 330). A suite of assays  has  now  been  developed  for  characterisation  of  concentration  (which  confirmed  the  low  and  standard  dosing),  and  future  batches  are  all  released  with  a  specification  dose  of  3·5–6·5 × 10¹⁰  viral  particles,  and  this was used for the booster doses in the efficacy analysis presented here.

One thing that I had been looking for is how well the vaccine prevents severe disease:

More than 21 days after their first dose, ten participants were  hospitalised  due  to  COVID-19  (defined  as  WHO  clinical  progression  score  ≥4),  two  of  whom  were  assessed  as  having  severe  COVID-19  (WHO  score  ≥6),  including one fatal case. All ten cases were in the control group (table 5).

So, with limited data (only 10 events), it does look like both the standard and low dose vaccines were effective in preventing serious COVID-19.

BC

[Goose]

https://marlin-prod.literatumonline.com/...326611.pdf


It explains how some individuals came to receive a half-dose for their initial dose:


<snip>

One thing that I had been looking for is how well the vaccine prevents severe disease:

More than 21 days after their first dose, ten participants were  hospitalised  due  to  COVID-19  (defined  as  WHO  clinical  progression  score  ≥4),  two  of  whom  were  assessed  as  having  severe  COVID-19  (WHO  score  ≥6),  including one fatal case. All ten cases were in the control group (table 5).

So, with limited data (only 10 events), it does look like both the standard and low dose vaccines were effective in preventing serious COVID-19.


BC

So overall pretty good news. Seems they are going for the EUA with the data they have and do not think they will need another trial to get it. As I read the paper, efficacy was a little "muddled", but ranged from 62.5% to 90%, depending on the protocol. Not perfect, but useful. The total lack of severe disease in the treated group is encouraging even with small N.

[Goose]

https://marlin-prod.literatumonline.com/...326611.pdf


It explains how some individuals came to receive a half-dose for their initial dose:


<snip>

One thing that I had been looking for is how well the vaccine prevents severe disease:

More than 21 days after their first dose, ten participants were  hospitalised  due  to  COVID-19  (defined  as  WHO  clinical  progression  score  ≥4),  two  of  whom  were  assessed  as  having  severe  COVID-19  (WHO  score  ≥6),  including one fatal case. All ten cases were in the control group (table 5).

So, with limited data (only 10 events), it does look like both the standard and low dose vaccines were effective in preventing serious COVID-19.


BC

So overall pretty good news. Seems they are going for the EUA with the data they have and do not think they will need another trial to get it. As I read the paper, efficacy was a little "muddled", but ranged from 62.5% to 90%, depending on the protocol. Not perfect, but useful. The total lack of severe disease in the treated group is encouraging even with small N.

[BostonCard]

I believe they are planning another trial (or at least they were):

https://www.reuters.com/article/us-healt...SKBN28620H

The question is whether what they have now is sufficient to get an EUA.  I would guess so, based on the stated goalposts (>50% efficacy and lower bound of the CI > 30%), which they meet.  Given that it offers the best chance to mass vaccinate quickly, I think it is probably worth moving forward with it.  But I would like to see a three arm trial of half-dose versus full-dose versus placebo (or at least the half-dose versus placebo) to verify the ~90%.

https://www.wsj.com/articles/astrazeneca...1607443250

AZ/Oxford will indeed submit the data.

BC

[BostonCard]

I believe they are planning another trial (or at least they were):

https://www.reuters.com/article/us-healt...SKBN28620H

The question is whether what they have now is sufficient to get an EUA.  I would guess so, based on the stated goalposts (>50% efficacy and lower bound of the CI > 30%), which they meet.  Given that it offers the best chance to mass vaccinate quickly, I think it is probably worth moving forward with it.  But I would like to see a three arm trial of half-dose versus full-dose versus placebo (or at least the half-dose versus placebo) to verify the ~90%.

https://www.wsj.com/articles/astrazeneca...1607443250

AZ/Oxford will indeed submit the data.

BC

[Goose]

I believe they are planning another trial (or at least they were):

https://www.reuters.com/article/us-healt...SKBN28620H

The question is whether what they have now is sufficient to get an EUA.  I would guess so, based on the stated goalposts (>50% efficacy and lower bound of the CI > 30%), which they meet.  Given that it offers the best chance to mass vaccinate quickly, I think it is probably worth moving forward with it.  But I would like to see a three arm trial of half-dose versus full-dose versus placebo (or at least the half-dose versus placebo) to verify the ~90%.

https://www.wsj.com/articles/astrazeneca...1607443250

AZ/Oxford will indeed submit the data.

BC

You raise an interesting question. The totality of their existing trials seems to justify an EUA, but for exactly what? From what I read, it would be the full dose both times, because there isn't as much data on the half followed by full? Yet the latter seems more promising (counter intuitive as that may be). A full study including a single dose as a fourth arm might be interesting. As was pointed out, the durability of immunity etc. is unknown for a single dose because everybody got a second.

[Goose]

I believe they are planning another trial (or at least they were):

https://www.reuters.com/article/us-healt...SKBN28620H

The question is whether what they have now is sufficient to get an EUA.  I would guess so, based on the stated goalposts (>50% efficacy and lower bound of the CI > 30%), which they meet.  Given that it offers the best chance to mass vaccinate quickly, I think it is probably worth moving forward with it.  But I would like to see a three arm trial of half-dose versus full-dose versus placebo (or at least the half-dose versus placebo) to verify the ~90%.

https://www.wsj.com/articles/astrazeneca...1607443250

AZ/Oxford will indeed submit the data.

BC

You raise an interesting question. The totality of their existing trials seems to justify an EUA, but for exactly what? From what I read, it would be the full dose both times, because there isn't as much data on the half followed by full? Yet the latter seems more promising (counter intuitive as that may be). A full study including a single dose as a fourth arm might be interesting. As was pointed out, the durability of immunity etc. is unknown for a single dose because everybody got a second.

[BostonCard]

The hand-waiving argument I've seen for the half dose is that the full dose produces a vigorous response against the viral vector (the chimpanzee adenovirus) so that when the booster is injected, it is destroyed before it can ever enter cells and thus the spike proteins are never expressed and don't produce an immune response.

BC

[BostonCard]

The hand-waiving argument I've seen for the half dose is that the full dose produces a vigorous response against the viral vector (the chimpanzee adenovirus) so that when the booster is injected, it is destroyed before it can ever enter cells and thus the spike proteins are never expressed and don't produce an immune response.

BC