【論文 開発中のSARS-CoV-2ワクチン】と【日経記事 新型コロナのワクチンは「パンドラの箱」か】(2020.10.2作成)

Florian Krammer @florian_krammer

93) Neutralizing antibody responses were measured in three different assays and appeared to be OK robust after one shot (1:50-1:100 range) with some increase after the second shot (>1:100). Similar to CanSino, there were quite a few side effects. One group was even given...

Florian Krammer @florian_krammer

94) paracetamol to see if this would alleviate the side effects but it didn't seem to do much. The study design included as licensed vaccine as placebo and so the differences in reactogenicity became nicely visible. Again, there are no real safety concerns but interferon driven

Florian Krammer @florian_krammer

95) side effects might be unpleasant. This vaccine is far in Phase III trials and will likely also become available via Serum Institute of India. thelancet.com/journals/lance…

Florian Krammer @florian_krammer

96) I forgot something important about the CanSino vaccine. It is now widely used within the Chinese military and is also in Phase III trials.

Florian Krammer @florian_krammer

97) Now, let's move to Moderna's mRNA-1273 mRNA-based candidate. Data from a a phase I, open-label, dose-escalation trial is available. Doses used were 25 μg, 100 μg and 250 μg in a prime-boost regimen. The vaccine encodes the spike with two stabilizing prolines.

Florian Krammer @florian_krammer

98) The vaccine was given twice in a 4 week interval. After the first vaccination, not much neutralizing antibody was induced, but titers post boost were pretty respectable in the 1:339.7 and 1:654.3 range (that's good!). T-cell responses were also detected, especially....

Florian Krammer @florian_krammer

99) CD4 T-cells. The safety profile was OK with solicited systemic events were reported in 33%, 67% and 53% of individuals after the prime dose and in 54%, 100% and 100% of individuals after the booster for doses of 25 μg, 100 μg and 250 μg, respectively.

Florian Krammer @florian_krammer

100) There wasn't much fever after the first dose but it was reported in 40% and 67% of individuals after the booster at doses of 100 μg and 250 μg - which seems high. Again, these are interferon driven self-resolving side effect that are unpleasant but not dangerous.

Florian Krammer @florian_krammer

101) This vaccine candidate is currently being evaluated at the 100 μg dose in phase III clinical trials in adults, including those in older age groups. nejm.org/doi/full/10.10…

Florian Krammer @florian_krammer

102) The second frontrunner with an RNA vaccine is Pfizer. They did not just evaluate one in the clinic, no, they tested at least two. BNT162b1 encodes a trimeric RBD, BNT162b2 encodes a full length spike with the two stabilizing prolines. Pfizer initially published a paper on...

Florian Krammer @florian_krammer

103) BNT162b1 only (below), but than published a comparison of the two vaccine types in older and younger individuals and I will focus on that data here. nature.com/articles/s4158…

Florian Krammer @florian_krammer

104) So, they used BNT162b1 and BNT162b2 at 10, 20, 30 ug doses (BNT162b1 as also tested at 100ug but the safety profile wasn't good so it was dropped) in a prime-boost regimen with a three week interval. They also stratified data by age groups 18-55 and 65-85.

Florian Krammer @florian_krammer

105) Neutralizing antibody levels were dose dependent with, but levels seemed to be comparable across the two vaccine groups. Similar to the Moderna vaccine, not much of a neutralizing response was induced by the prime but levels rose to respectable 1:70-1:360 in the younger ...

Florian Krammer @florian_krammer

106)...age group and lower 1:40-1:80 in the 65-85 age group, very similar to what has been observed by Sinovac. The safety profile was similar to Moderna's vaccine. Side effects included fever, fatigue and chills, especially after the second dose. Interestingly, side effects....

Florian Krammer @florian_krammer

107) were lower in the older age group. BNT162b2 was finally selected for further development. This vaccine is far in Phase III trials. medrxiv.org/content/10.110…

Florian Krammer @florian_krammer

108) The last one to discuss is Novavax. Novavax is using a recombinant spike based vaccine that is produced in insect cells and adjuvanted with Matrix M. The available data is from a randomized, observer-blind, placebo-controlled phase I trial. Participants were given...

Florian Krammer @florian_krammer

109) ....two doses (in a 3 week interval) of nonadjuvanted vaccine at 25 ug, of adjuvanted vaccine at 5 or 25 ug or a single dose of adjuvanted vaccine at 25 ug. The adjuvant use is a saponin-containing and called Matrix M. Nonadjuvanted vaccine let to low titers after the

Florian Krammer @florian_krammer

110) second dose (1:41), but adjuvanted vaccine given twice at either dose let to very high titers in the 1:3000 to1:4000 range. Adjuvanted vaccine given once resulted in lower titers (1:128). Good CD4 T-cell responses were also detected. Tolerability was good and fever was rare.

Florian Krammer @florian_krammer

111) This candidate just entered Phase III trials in the UK. The paper can be found here. nejm.org/doi/full/10.10…

Florian Krammer @florian_krammer

112) There is one more candidate that has data, a AdV5/AdV26 prime-boost combination from Gamaleya Institute in Russia. This vaccine was licensed after Phase II trials which is in my opinion unethical. There are also some questions about the data in their paper, so.....

Florian Krammer @florian_krammer

113) I'll let judge everybody for themselves. thelancet.com/journals/lance… and here a little bit of criticism: cattiviscienziati.com/2020/09/07/not…

Florian Krammer @florian_krammer

114) Now, as with the NHP data, it is really hard to directly compare neutralization titers and T-cell results since different assays were used. Any comparison needs to be taken with a grain of salt. However, a certain picture in terms of immunogenicity and side effects emerges:

Florian Krammer @florian_krammer

115) In terms of immunogenicity, inactivated and AdV5-based vaccines seem to rank the lowest, followed by ChAdOx1-based vaccines and mRNA vaccines, and finally adjuvanted, protein-based vaccines, which show the best performance.

Florian Krammer @florian_krammer

116) Reactogenicity seems to be lowest in inactivated and protein-based vaccines, followed by mRNA vaccines, with vectored vaccines having the highest rate of side effects.

Florian Krammer @florian_krammer

117) Now, in general all of this looks good and I am amazed how well and fast this moves. But I still want to discuss a few topics (and I assume there will be a lot of debate about them).