This article discusses the possible mechanisms of the rare blood-clotting side effect of COVID vaccines, and which vaccines are more likely to elicit these rare events. In a linked article, we discuss what this means for investors in small and mid-cap COVID vaccine companies.*
On April 13, the U.S. CDC and FDA paused the emergency use of the Johnson & Johnson (J&J) COVID vaccine due to a rare blood clotting disorder that developed in some people who were vaccinated (6 women between 18 and 48 from the first 6.8 million doses of the J&J vaccine administered). With growing evidence that the severe blood clotting disorder is a real side effect of the J&J vaccine, what does this mean in terms of the likelihood of success and valuations of small/mid-cap COVID-19 vaccine players in our database?
First, what do we know about these rare blood clotting side effect cases?
Although the exact molecular mechanism of the rare blood clotting side effect is unknown, it appears to be associated with a strange condition in which platelets, the blood component at the center of blood clotting, are actually extremely low, sometimes to the point of a condition called thrombocytopenia. Ordinarily, low platelet counts are associated with bleeding, not increased blood clotting. But the people who had this rare side-effect of the J&J vaccine, appear to have this strange condition of low platelet counts but increased blood clotting in unusual locations such as the brain (https://www.cdc.gov/media/releases/2021/s0413-JJ-vaccine.htmL).
This strange phenomenon appears similar to the rare blood clotting disorder called heparin-induced thrombocytopenia (HIT) and the rare side effects seen with the Astra Zeneca (AZN) vaccine (https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood).
So is this side-effect a "class effect" of Adenoviral vector-based vaccines?
The obvious common link between the J&J vaccine and the Astra Zeneca vaccine is that they are both adenoviral vectors. Thus, a question is whether this is a class effect, meaning, whether this is an effect of all adenoviral vector COVID vaccines. The EMA originally concluded that the side effects were unlikely due to the adenovirus vector and more likely related to the thrombotic complications observed with COVID-19 infections, although after learning of the J&J rare side effects, the EMA now indicates it is uncertain whether this is a class effect (Watch the EMA's press conference from 4/20/21).
Revelation that this rare side-effect may occur at some level with all COVID vaccines.
However, at the EMA's 4/20/21 press conference, it was disclosed that as of April 13, 2021 there have now been 8 cases reported with the J&J vaccine and 287 with the AZN vaccine. More surprisingly, it was reported that there have been 25 cases reported with the Pfizer mRNA (no adenovirus) vaccine, and 5 cases with the Moderna vaccine (no adenovirus). Thus, this is not exclusively an adenovirus vector side effect.
However, if we look at some case numbers, there seems to be a higher prevalence with adenoviral vectors, although there is a lot of potential noise in this data. Since we could not get accurate worldwide dose data by brand, we have the following:
AZN vaccine - 4.7/M doses (169 cases of the 34M doses in Europe as of 4/4/21)#
J&J vaccine - 1.9/M doses (15 cases out of 8M doses in the U.S. as of 4/13/21)##
Pfizer vaccine - <0.18/M doses (25 cases out of over 140.6M doses worldwide as of 4/21/21)###
Moderna vaccine - <0.05/M doses (5 cases out of over 90.8M doses worldwide as of 4/13/21)###
From the above early data, it appears that the adenoviral vector vaccines may have a 10 fold or higher level of this rare side effect. However, there needs to be a lot of caution in this data. For one, the European Union has been on the close lookout for these rare thrombotic events in AZN vaccinated people, whereas the data for the other vaccines is from routine monitoring/surveillance for side-effects. With a closer watch for abnormal thrombosis those numbers could go up for the other vaccines. However, the fact that there have been 0 reported cases in the U.S. for the Pfizer or Moderna vaccines, and 8 in less than 1/10th of the J&J vaccines administered, suggests that the difference in rates of this event is real.
Furthermore, this data suggests that COVID vaccines as a class, exhibit this rare event. There have been a number of proposed mechanisms (See the European regulatory agency's (EMA's) discussion on this topic) and this was before the more recent data finding this rare event in at least 4 of the major COVID vaccines. It was recently shown that all of the tested people that had the blood clotting side effect with the J&J COVID vaccine (4 were tested out of the initial 6 J&J side-effect patients) and the vast majority of those tested that had the AZN side effect, had very high levels of autoantibodies against a protein called Platelet Factor 4 (PF4) (See https://www.nejm.org/doi/full/10.1056/NEJMoa2104840?query=recirc_curatedRelated_article and https://www.nejm.org/doi/full/10.1056/NEJMoa2104882), which is released by damaged platelets. Interestingly, adenoviral vectors have been reported to bind and damage platelets.
Thus, possibly not surprisingly, this is an auto-immune event driven by these anti-PF4 autoantibodies. And if the basis relates to autoantibodies, as suggested by the PF4 antibody publication cited above, it may not be a coincidence that strange blood clotting issues are also seen in some severe COVID patients (as the EMA concluded as well). It has been postulated that the spike protein may activate and/or damage platelets (SOURCE). Furthermore, the rare side effect appears to be much more common in women than men. Women are known to have a higher propensity for autoimmune disorders. So despite the surprising conclusion by the European regulators that the data was too early to conclude there is higher risk in women then men (EMA's press conference from 4/20/21), this could make sense if it is an auto-immune-based side effect. Furthermore, vaccine to vaccine differences could relate to different spike proteins used in the vaccines.
See Table 1 below from "Why are autoimmune diseases more prevalent in women?"
Are mRNA vaccines superior to other types of vaccines?
From the side-effect prevalence above, it is quite possible that mRNA vaccines have a lower risk of this rare blood clotting side effect. Furthermore, these vaccines have had excellent efficacy. Thus, it appears from this early perspective, that these mRNA vaccines have a safety advantage over the J&J and AZN vaccines, and possibly viral-based vaccines in general. Of course, the biggest advantage of the mRNA vaccines appears to be the speed at which they can be developed, which has been especially apparent in this pandemic. All in all, mRNA vaccines are coming out of this pandemic as a new superstar vaccine technology.
Other vaccine technologies
Another vaccine technology to consider are protein vaccines, such as NVAX's COVID protein nanoparticle vaccine (See IQ card), and plasmid DNA vaccines with electroporation, such as INO's plasmid DNA COVID vaccine. For INO, we saw data from INO-4800, their COVID vaccine, last week. The data looked competitive, but the market did not appear to be impressed, likely because the market feels that INO is too far behind in the timeframe for its first emergency use authorization. Protein-based vaccines have the advantage of decades of safety data. However, each vaccine is unique and we don't have enough safety data with NVAX's COVD vaccine candidate to precisely enough compare it to the adenoviral vector and mRNA vaccines. We should get more safety data from NVAX some time this month when it reports out its Phase 3 results.
Regardless of the mechanism, it appears highly likely that the J&J vaccine will be cleared again for vaccinations this week in the U.S., although it will almost certainly come with warnings (as in Europe) and/or restrictions, likely against people that are 55 or under, and possibly especially females. This side effect is very rare in these vaccines, and the vaccines will save at least 100,000s if not millions of lives from this pandemic.
Check out our free blog post, or more detailed and informative forum post if you are a biopharma investor interested in Covid vaccine companies. To access our forum post, just go to http://BPIQ.com and sign up for a free 30-day trial (no credit card required) and get instant access to all this information.
# See EMA report on AZN vaccine HERE
###EMA's press conference from 4/20/21 and minimum number of worldwide doses of Pfizer and MRNA vaccines calculated from U.S., German, and certain other countries FOUND HERE. and Israel data FOUND HERE. In U.S. CDC reported that there are 0 confirmed cases of thrombosis with thrombocytopenia, with either the Pfizer or Moderna vaccines.
*Footnote: Our article was originally posted on 4/18/21. If you are a small and mid-cap biopharma investor, see our accompanying article regarding what this Covid vaccine safety data might mean for other companies with Covid vaccine candidates.Originally posted on 4/18/21 but then split into 2 articles on 4/21/21. Updated on 4/19/21 to correct typos and add ALT to the adenoviral vector COVID vaccine list. Updated on 4/20/21 after listening to EMA press release today on the J&J vaccine rare safety issues. Updated on 4/23/21 with updated J&J thrombosis data from CDC meeting.