After Friday comments by Trump that the US would be back in business with or without a vaccine, a number of other world leaders were suddenly warning of and
contemplating a world without an effective Covid19 vaccine. This made me wonder whether early clinical data from Moderna Inc’s
closely watched mRNA Covid19 vaccine were being shared between Western governments.
Indeed, first data from the program were released right after the weekend and by any
standard of normal vaccine development, development of the mRNA-lipid
nanoparticle (LNP) mRNA-1273 would have been terminated for safety in favor of an alternative, hopefully safer candidate.
Problematic safety signals
The primary objective of phase I studies is safety. The study tested 2 monthly muscle injections each of 3 ascending doses (25ug,
100ug, and 250ug). A secondary objective was to evaluate immunogenicity, although unlike with better known entities like influenza virus, the extent and nature of the required immunogenicity to protect people from
getting infected or develop severe disease is unknown for the novel coronavirus.
The highly selective and unnecessarily descriptive interim
phase I press release, disclosed not just one, but four grade 3 immune
toxicities in the small sample of 45 healthy volunteers. Of note, 3 of those were systemic
manifestations.
Side effects reminiscent of serious LNP safety issues
This is very troublesome for a nucleic acid LNP, because from the
history of such therapeutics it is known that they can elicit highly variable
innate immune responses in the human population. At worst this can result in anaphylactic shock which, if unsupervised, can result in death and is also why systemically delivered LNPs are often used with immunosuppressive pre-medication and reserved for severe diseases (e.g. RNAi drug ONPATTRO for TTR amyloidosis).
It would therefore have been extremely informative and important to disclose whether the reported systemic adverse events were correlated and temporarily linked to the LNPs leaking
out from the injection site of the muscle into systemic circulation, or whether
they were due to a vigorous immune response to the generated antigens. The latter immune reactions would be of
lesser concern and in a way complimentary of efficacy, but I guess Moderna would have said so if this had been the case.
In acknowledgment of the safety signals, Moderna Inc. has reduced the
anticipated dosages for the upcoming phase II study from the originally
envisaged 50ug and 250ug to 50ug and 100ug and I wouldn’t be surprised if the
25ug dose were the go-to dose in the eventual pivotal phase III study of this chaotic development plans.
So the question comes down to whether a dose 4x lower than where grade 3
immune toxicities were starting to be seen in a small study of healthy
volunteers (and you can be certain that many more vaccine-related grade 1
and 2 adverse events were not disclosed yesterday) gives you sufficient
comfort for such a vaccine to be used in billions of genetically and otherwise (health, age etc) heterogeneous
people in less supervised settings.
If you want to completely destroy public confidence in vaccines, this may
be the way to do it.
But let’s be generous and assume that 25ug of mRNA-1273 does not kill too many. The question then would be whether the mRNA approach and such a low dose provided sufficient immunity to SARS-CoV-2?
No substantial evidence of efficacy
Don’t hold your breath
For 8 subjects, 4 each at 25 and 100ug, descriptive immunogenicity data
were provided. At 25ug, ‘levels of
binding antibody were at the levels seen in convalescent sera’ at day 43, 2
weeks following the booster injection.
This at first sight sounds promising, but is actually not very helpful
because antibody responses in naturally infected people is known to be highly divergent
and in fact more pronounced in those with a severe course of the disease.
To further suggest predictive efficacy, Moderna cites in-house mouse
challenge studies where antibody titers corresponding to those in the phase I study were said to be protective in mice. Given that SARS-CoV-2 does not replicate well
or at all in wild-type mice (and consequently does not lead to disease there), this comment is meaningless
without disclosing the mouse strain used.
And how about disclosing much more meaningful monkey challenge studies
that Moderna Inc surely must have done just as the Oxford adenovirus group and Sinovac Biotech have done?
Corporate games
Overall, in a time when collaboration and transparency is critical and early publications
are possible and routine, not providing hard antibody level data, omitting whether there were cellular immune responses etc, and without a more detailed list and description of side
effects can only be explained by a desire to exploit this for maximum financial gain.
Accordingly, Moderna did not hesitate even a day to pull in over $1.3B in a stock offering from what must be generalist investors unfamiliar with drug development. At the same time, the newly minted Covid19 vaccine
czar Moncef Slaoui divested his more than $10M worth of Moderna stock options effective Tuesday morning- that is before
the public release of the full data. This insider trade masquerading as washing his hands in innocence is really the icing on the cake.
