And now we have more data on the CanSino vaccine, another adenovirus vector (but this one using Ad5, a much more common one in the human population). Their initial Phase I data are discussed here. So what else do we know now?
Well, that one was open label and non-randomized, whereas this one is fully controlled. It also is much larger, and has a wider range of ages and should be more of a real-world look. There are two doses (5 x ten to the tenth, 129 patients, and 1 times ten to the eleventh viral particles, 253 patients, and a comparison to a placebo group of 126 patients as well). 52% of them had high pre-existing immunity to adenovirus-5, which has always been a concern with this effort.
There were no serious adverse events in either dosing group, and the events that did take place were exactly the sort of thing we’ve been seeing before – pain and soreness at the injection site, general fatigue and aches, mild fever. It doesn’t look like we’re going to get away from any of those, so we should all remind ourselves that it damn well beats getting the coronavirus.
Both doses produced similar titers of neutralizing antibodies, as it turns out, and these kicked in sometime between Day 14 and Day 28. But when you look at the half of the subjects who already had high levels of antibodies to the Ad5 vector, you find that their titers were 2 to 3 times lower than the ones who didn’t start out that way. The patients who were older than 55 also showed noticeably lower antibody response – still above placebo, true, but nowhere near as robust as the younger patients. Older patients were more likely to have the Ad5 antibodies, which is surely a good part of the reason for this. None of the data in the paper go out past 28 days, so we can’t say much of anything about whether there’s a dropoff in antibody titers.
Both doses of vaccine produced a similar T-cell response, and in that case there’s no real difference between the ones with higher pre-existing Ad5 antibodies and the lower ones. These data are only shown as a snapshot at Day 28. Only about 1% of the patients showed any T-cell response at the baseline pre-dosing, interestingly. Another thing to note: the age of the patients seemed to make no difference in the T-cell response, as opposed to what was seen with the antibody levels. There are no data on CD4+ versus CD8+ cells, unfortunately.
Overall, then, this is a useful but limited publication. It tells us more about the CanSino vaccine’s profile, but it also raises some worries about just what everyone was already worried about: the pre-existing Ad5 immune response. This should come as no surprise to anyone, and the paper states clearly that this is their biggest concern going forward. In the Chinese population, about 50% of the population is in that category – in India it’s 80%, and in the US around 30%. The question is what differences one might see in the Phase II efficacy readouts. Remember, giving a booster shot with one of these viral-vector agents is quite problematic – after the first dose, the number of your patients who have neutralizing antibodies to the vector is now 100%. One the other hand giving one shot instead of two is potentially a big advantage – but only if that one shot is enough. Yet again, we’re going to have to let this shake out in Phase II. Maybe it won’t make a difference, but. . .given these concerns, if I were a betting man – perish the thought – this vaccine is not where I would be putting my money just now.
It’s immensely heartening that they measuring and reporting more than circulating IgG response, and that they’re breaking out responses by age.
I remains unlikely that one can effectively boost an adenovirus-based vaccine; immunity to the vehicle would be expected to neutralize the booster w/o visible benefit.
“I remains unlikely that one can effectively boost an adenovirus-based vaccine; immunity to the vehicle would be expected to neutralize the booster w/o visible benefit.”
They have experience in this regard , and it suggests that a prime-boost strategy may work :
“The adenovirus 5-vectored Ebola vaccine of 1·6 × 1011 viral particles was highly immunogenic and safe. The lower dose of 4·0 × 1010 viral particles was also safe, but immunogenicity seemed to be more vulnerable to the pre-existing immunity of adenovirus 5. A homologous priming-boosting regimen with adenovirus type-5 Ebola vaccine at 6 months interval was able to elicit greater antibody responses with longer duration. These results support an immunisation strategy to implement a booster injection for a more durable protection against Ebola virus disease.” ( Ref #13 in the new Lancet paper )
Ad antibodies would decline over time. If you wait long enough ( i.e. back to baseline Ad ab levels ) you may get a sufficient response to the boost.
Whats the advantage of using an adenovirus with a pre-existing immune response as opposed to, say, Oxford’s approach? That seems like an odd choice to make when pursuing a vaccine candidate.
I can only agree. The main advantage would probably have been speed – they had this technology ready to go, so they went with it.
If your vaccine doesn’t work in patients who are immune to the vector, you’ll fail your phase II trial with a common vector. If you used a rarer vector, you might roll out a vaccine that stops working if the population becomes more commonly immune to the vector. I could see the argument that, if a vaccine depends on being vector-naive, that’s maybe an important flaw, and they might want to gate acceptance on that not being an issue.
In the case of a rare vector, could some patients be infected with a “dummy” version of that vector, one that doesn’t carry the coronavirus immunity, and develop vector immunity before administering the actual vaccine?
Even if that were possible, I suppose that would slow down covid trials, as you’d have to wait for patients to develop immunity to the adenovirus.
The Vaxart pill vaccine also uses the AD5 vector, but they claim it “evades” the anti-vector immunity problem. So, AD5 just might work in this case.
from “seekingalpha.com:”
“VXRT’s vector is produced in their proprietary enteric-coated tablets, which deliver their Ad5 vector to the small intestine. VXRT believes that orally-delivered Ad5 vector will trigger much lower level of neutralizing antibodies than injectable Ad5-vector vaccines. So far their phase 1 data supports this hypothesis. This significant safety advantage would allow for repeated dosing (e.g. annual vaccination).”
These oral/mucosal delivery routes are quite interesting, and I’m glad that people are working on them. I hope that there’s enough money and capacity to get some of them into solid Phase II/III trials.
One quick question for everyone: early studies on traditional vaccines have shown that T-cell response is dependent on the type of adjuvant used. The vaccines near P3 trials for COVID-19 are either mRNAs of viral vectors, which I assume are without adjuvants. Are the T-cells responses robust enough?
One concern I have is the lack of enrollment of older (65 and older) patients as this group is most likely to be vaccinated first once and if available.
As I understand it, the mRNAs themselves act as adjuvants, a two-mints-in-one strategy.
Is the pfizer/biontech T-cell response directed to the Covid Corona virus (eg, viral antigen and in in vitro assays), Or a generalized measure of T-cell ? Could this T-cell response be to just the Adeno Ad5 shell component of the vaccine?
meant to say edit CanoSino not pfizer/biontech
I’m a layman, so sorry if this is a dumb question.
If the suggestion is that this particular vaccine would be effective, but just in people who don’t already have the Ad5 antibodies, then is there some ready way to identify who has the Ad5 antibodies?
Put another way: suppose we get very lucky and several vaccines work. We presumably would want to use what we have as efficiently as possible. If I can be identified as someone that doesn’t have Ad5 antibodies then I could take this one and as such free up a dose of another vaccine for someone that does have Ad5 antibodies.
Or does it not work that way?
No, it definitely could. Detecting Ad5 antibodies is no great problem. . .
“This makes one think, as many have been wondering, that T-cell driven immunity is perhaps the way to reconcile the apparent paradox between (1) antibody responses that seem to be dropping week by week in convalescent patients but (2) few (if any) reliable reports of actual re-infection. That would be good news indeed.”
In: New Data on T Cells and the Coronavirus
And:
“Both doses of vaccine produced a similar T-cell response, and in that case there’s no real difference between the ones with higher pre-existing Ad5 antibodies and the lower ones” … “Another thing to note: the age of the patients seemed to make no difference in the T-cell response, as opposed to what was seen with the antibody levels. There are no data on CD4+ versus CD8+ cells, unfortunately.”
In this post.
“This makes one think, as many have been wondering, that T-cell driven immunity is perhaps the way to reconcile the apparent paradox between (1) antibody responses that seem to be dropping week by week in convalescent patients but (2) few (if any) reliable reports of actual re-infection. That would be good news indeed.”
In: New Data on T Cells and the Coronavirus
And:
“Both doses of vaccine produced a similar T-cell response, and in that case there’s no real difference between the ones with higher pre-existing Ad5 antibodies and the lower ones” … “Another thing to note: the age of the patients seemed to make no difference in the T-cell response, as opposed to what was seen with the antibody levels. There are no data on CD4+ versus CD8+ cells, unfortunately.”
In this post.
These information combined wouldn’t make this approach a good bet?
This is the complete one.
Is this the vaccine that was reportedly already being given in China to military personnel and businesspeople traveling outside China?
(And is that definitely happening – and, if so, what does it mean about the Chinese government’s confidence in the vaccine’s efficacy/safety?)
Seems so: https://www.reuters.com/article/us-health-coronavirus-china-vaccine/cansinos-covid-19-vaccine-candidate-approved-for-military-use-in-china-idUSKBN2400DZ
I’d guess that means it *probably* won’t kill patients. I don’t think it says much about efficacy, as barely-better-than-placebo would still be worth taking.
Well, assuming efficacy isn’t negative (e.g. antibody-dependent enhancement), yeah I guess that’s true.
If there is no more Covid19 in China, how are they going to tell if it works? (or is there still Covid19?)
They are doing trials in Brazil where there are ample cases.
Blue-check “thought leader” sawing off the tree limb she’s sitting on. We’ve seen it over and over again , on masks , asymptomatic spread , D Vs G transmissibility , etc. The sad thing is , even after these people crash to the ground in a heap once the data solidifies , they’re still viewed as experts. No humility , and no appreciation of the precautionary principle :
https://twitter.com/angie_rasmussen/status/1285329888698720256
Can’t they just pre-test antibodies on people, then calibrate dose accordingly? Higher titers of AD5 antibodies corresponded to needing a higher dose, but also better safety profile. It’s more labor, but if it’s the only vaccine they have, would be worth it. Can dial a dose based upon the AD5 and evade this issue maybe?
Prelim report showing seroprevalence of 71% in Iquito , Peru. If confirmed , this would be the highest attack rate observed in any large population. Not much ammunition for the “dark matter” nutters here, but the people of Iquito could be close to being out of the woods if immunity and the predicted herd effect threshold play nice :
https://twitter.com/isabelrodbar/status/1285456607065681921
The data for CD4+ and CD8+ secreting IFN, TNF and IL-2 have already been shown in the CanSino phase 1 paper from May. If you compare data from Figure 2 with data from Moderna’s phase 1 paper appendix (Figures S9, S10, S11) you will find CanSino’s vaccine candidate performs much better. CanSino’s value for CD8+ IFN (28 days, Middle dose) is more than ten times higher than Moderna’s value for CD8+ IFN (29 days, Middle dose). CanSino’s value for CD4+ IL-2 is 0,15 (28 days, Middle dose) whereas Moderna’s value for CD4+ IL-2 is only 0,027 (S1 peptide pool) and 0,055 (S2 peptide pool). In Table 3 CanSino’s vaccine shows 806 ELISA RBD antibodies (28 days, Middle dose) whereas Moderna’s vaccine shows only 93 ELISA RBD antibodies (29 days, Middle dose) as displayed in Table 2 of the phase 1 paper. We have already learned that Moderna’s candidate will not work without a boost. But even after the boost the ELISA antibodies are less in numbers than the antibodies being created after a single vaccination by CanSino’s vaccine.
CanSino’s vaccine shows also better ELISA antibody numbers than the ChAdOx1 from Oxford (Table S5, Appendix). The ChAdOx1 needs also a boost to create fair antibody numbers. CanSino also shows better performance in terms of IFN ELISpot response. The CanSino vaccine candidate is still in the race and nobody should underestimate it’s chances to win the race for the first approved corona vaccine.
….whereas Moderna’s vaccine shows only 93 ELISA RBD antibodies (29 days, Middle dose) as displayed in Table 2 of the phase 1 paper….
If I understand correctly in this case, the value of GMT 93231 is presented. or am I wrong?
It’s getting quite tricky to compare all the vaccines for responses and other attributes. Could do with a nice comparison table!
Can someone please explain whether its likely the T-cells ellicited by the different vaccines are all of one single type, recognising a single epitope or might there be a variety, recognising different sub parts of the antigen S protein? Apologies if its a dumb question
I’ll be putting one up after the J&J effort reports, definitely.
Fantastic – you’re a star!
Any idea on the other question? I am very interested in the T-cell response and really keen to learn more. Also, I want to understand re the relatively small % in all the trials with pre-existing T cells compared with all those other papers (34%, 40-50%, and the latest, 81%: https://www.researchsquare.com/article/rs-35331/v1%C2%A0) – is that because the vaccine trials are only looking at T-cells that react with the particular epitopes being used in the vaccines?
The use of inhaled formulation of interferon beta has shown encouraging effect in a phase 2 trial. Patients who received S-N-G-001 had a 79% lower risk of developing severe disease compared to placebo. This data is not peer reviewed and was carried on 100 patients but could be a viable treatment option.
In this study, we describe for the first time the interaction of integrin Mac-1 with CD147. We provide evidence that CD147 is a novel and relevant binding partner for Mac-1 on leukocytes and platelets. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226095/