【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

68)...routes with a relatively high challenge dose of 2.6x10^6 TCID50. If the vaccine was given twice, the animals lungs were completely protected, if the vaccine was given once, the lungs were partially protected. Not much protection was seen in the upper respiratory tract.

Florian Krammer @florian_krammer

69) I forgot, they also looked at T-cells and got a pretty good response. Here is the paper. Awesome work by @DrNeeltje and team at NIH's Rocky Mountain Lab. nature.com/articles/s4158…

Florian Krammer @florian_krammer

70) The next vaccine is also a viral vector, but this time and adenovirus 26 vector also expressing the spike protein and developed by Janssen. This vaccine was tested by Dan Barouch's group. I really liked that they made different spike versions and tested them in parallel.

Florian Krammer @florian_krammer

71) Animals were vaccinated once with the respective AdV26 vectors at a dose of 1x 10^11 virus particles expressing different spike variants. The best one was called S.PP which has two stabilizing prolines and the polybasic cleavage site deleted. We are going to...

Florian Krammer @florian_krammer

72)...focus on this one since this is the one selected for clinical development. After one shot neutralizing titers of 1:100 were reached. T-cells were measured as well but were low. The animals were then challenged with 10^5 TCID50 (lower than for AZ). Amazingly, the S.PP....

Florian Krammer @florian_krammer

73)...animals were protected from virus replication in the lower and upper respiratory tract after just one shot. Pretty cool but I am not sure one shot will work in humans. They are now in Phase III as well. nature.com/articles/s4158…

Florian Krammer @florian_krammer

74) This brings us to the Moderna mRNA candidate mRNA-1273. NHPs were given the vaccine twice at two different doses (10ug or 100ug). After the second dose, the animals developed substantial neutralizing antibody titers in the 1:501-1:3481 range. I mean, that's high....

Florian Krammer @florian_krammer

75) The animals also developed good CD4 and Tfh T-cell responses. They were challenged with 7.5x10^5 TCID50 of virus (much more than Janssen, a little less than AZ) and complete protection of the lung was observed in the high dose group. The high dose group also showed....

Florian Krammer @florian_krammer

76) ...little virus replication in the upper respiratory tract. These was some, but really little. As we all know, this vaccine is in Phase III as well now. nejm.org/doi/full/10.10…

Florian Krammer @florian_krammer

77) Finally, there is the Novavax data. Novavax uses recombinant spike adjuvanted with Matrix-M. They tested 2.5 or 25 ug of protein given twice in the NHPs. Neutralizing titers reached obscenely high 1:17,920 - 1:23,040. Upon challenge with 10^4 TCID50 (much lower than others)

Florian Krammer @florian_krammer

78)...they got complete protection of both the lower and upper respiratory tract. The paper can be found here: biorxiv.org/content/10.110…. There is also some more data in baboons.

Florian Krammer @florian_krammer

79) To summarize the NHP data: Different vaccines have different abilities to induce neutralizing antibodies. All vaccines protect the lung/lower respiratory tract but many only provide partial protection of the upper respiratory tract (we will get back to that).

Florian Krammer @florian_krammer

80) Also, different assays used, different challenge doses , different species (rhesus vs. cynos) and different readouts for detecting virus make direct comparisons different. But If I had to choose based on the data I'd take the AdV26 as prime and the Novavax vaccines as boost😜

Florian Krammer @florian_krammer

81) Now a short red wine break before we go into humans.

Florian Krammer @florian_krammer

82) OK, lets continue with humans, the very special primates. I'll again go by candidate/vaccine company.

Florian Krammer @florian_krammer

83) CoronaVac (inactivated SARS-CoV-2+aluminium hydroxide) by Sinovac. They published data from a randomized, double bling placebo controlled trial. 3 or 6 ug of vaccine were given twice, adjuvanted with alum. They used two intervals, either two weeks or four weeks.....

Florian Krammer @florian_krammer

84) They achieved non-impressive neutralization titers in the 1:30 to 1:60 range. But since e.g. the 50% protective titer for influenza is 1:40, this might be enough, who knows. The vaccine also seemed pretty safe with very few side effects.

Florian Krammer @florian_krammer

85) One interesting thing they did was to compare the neutralizing antibody response in younger adults and the 50-59 age group. The 50-59 group had marked lower immune responses. We will get back to that in the end. This vaccine is currently in Phase III. medrxiv.org/content/10.110…

Florian Krammer @florian_krammer

86) Sinopharm has published human Phase I and II data for a very similar vaccine. They evaluated 2.5, 5 and 10 ug in a three dose regimen in Phase I and then 5 ug in a two dose regimen in a two and three week interval in Phase II. The results are very similar to Sinovac.

Florian Krammer @florian_krammer

87) Neutralization titers post-boost reached 1:121-1:316. This vaccine is now also in Phase III. jamanetwork.com/journals/jama/…

Florian Krammer @florian_krammer

88) CanSino published two data sets with its AdV5 vector expressing the spike protein. The vaccine was only given once at 5x10^10 or 10^11 virus particles. It induce OK T-cell responses but neutralizing antibody responses were mediocre at best with titers of 1:18.3-1:19.5.....

Florian Krammer @florian_krammer

89) Preexisting immunity to AdV5 impacted negatively on the induced response, in a way this as expected. Since older people have more immunity to AdV5 it seemed to do worse in older people. This vaccine also had considerable side effects including:

Florian Krammer @florian_krammer

90) Fever, fatigue and headache, injection site pain etc. Grade 3 adverse reactions (mostly fever) were reported in 9% of individuals in the high-dose group. Not pleasant but maybe also not problematic. These are typically side effects triggered by vaccines that induce...

Florian Krammer @florian_krammer

91) innate immune response and the body responds how it would response to an infection, with interferon which makes us feel sick. These site effects are unpleasant but usually transient and not too concerning (they might be problematic in kids, more about that later).

Florian Krammer @florian_krammer

92) AstraZeneca's ChAdOx1 nCOV-19 (non-rep chimpanzee AdV expressing S) has data from a phase I/II, single-blind, randomized control trial. Vaccine was given at 5x10^10 virus particles once or twice (in a small subset). The vaccine induced good T-cell responses.