Covid-19: EMA defends AstraZeneca vaccine as Germany and Canada halt rollouts

Dear Editor

Recently several countries have suspended vaccinations with the AstraZeneca Covid-19 vaccine (AZV). Concerns of national regulators particularly regarded cerebral venous sinus thrombosis (CVST). Until now, there were about 62 CVST after AZV across Europe, 14 of them (22.6%) were fatal. Although authorities stated that benefits continue to outweigh associated risks, some countries decided to restrict vaccinations with AZV.[1] In the developed countries, as soon as the majority receives vaccinations, future immunizations will probably be performed primarily with mRNA-based products. There is, however, an important logistic problem associated with such vaccines. They require storage at very low temperatures, which in many countries is not feasible. Thus, viral vector vaccines, such as AZV, which require only regular fridges, will probably be still needed to curb Covid-19 in remote locations.

Therefore, the question how AZV can trigger CVST, and whether the incidence of these adverse events could be reduced, seems important. Currently, experts think that although causal relationship between AZV and CVST has not been proven, it could results from hypercoagulability already present in some vulnerable groups, like younger women. In the not yet published study (preprint) (https://www.researchsquare.com/article/rs-362354/v1) a laboratory profile of patients presenting with CVST after AZV resembled that of heparin-induced thrombocytopenia. However, a majority of them did not receive heparin. In addition, mortality rate among AZV-associated CVST patients is much higher than in normal CVST (4%).[2] This suggests that such events are not normal thromboses, but rather immunothromboses resulting from excessive production of neutrophil extracellular traps (NETs) triggered by the vaccine. It has already been found that SARS-CoV-2 spike protein (the gene coding for this protein is a part of AZV) can evoke release of NETs.[3] NETs are also produced in the settings of heparin-induced thrombocytopenia,[4] which may explain the laboratory profile of the above-discussed CVST patients.

Another unsolved problem regards the question - why AZV-associated thromboses particularly affect cerebral sinuses. Perhaps, this complication occurs in patients with anatomical variants of these veins resulting in venous stasis in the decubitus body position.[5,6] Activation of neutrophils in the settings of blood stasis is a well-known phenomenon. Retrospective analysis of venograms of CVST patients could validate this conjecture.

Hypothetically, prophylaxis against potentially fatal CVST with dipyridamol could be a solution. This pharmaceutical agent is characterized by agonistic activity on the neutrophil adenosine A2A receptor, which in turn reduces release of NETs.[7] This drug is inexpensive and such a prophylaxis should not significantly increase costs of vaccination.

References:
1. Dryer O. Covid-19: EMA defends AstraZeneca vaccine as Germany and Canada halt rollouts. BMJ 2021;373:n883.
2. Haghighi AB, Edgell RC, Cruz-Flores S, et al. Mortality of cerebral venous-sinus thrombosis in a large national sample. Stroke 2012;43:262-264.
3. Youn YJ, Lee YB, Kim SH, et al. Nucleocapsid and spike proteins of SARS-CoV-2 drive neutrophil extracellular trap formation. Immune Netw 2021;21:e12.
4. Perdomo J, Leung HH, Ahmadi Z, et al. Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia. Nat Commun 2019;10:1322.
5. Simka M. Chronic cerebrospinal venous insufficiency: current perspectives. J Vasc Diagn 2014; 2:1-13.
6. Simka M, Latacz P. Numerical modeling of blood flow in the internal jugular vein with the use of computational fluid mechanics software. Phlebology 2021, doi: 10.1177/0268355521996087.
7. Liu X, Li Z, Liu S, et al. Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19. Acta Pharm Sin B 2020;10:1205e1215.

Dear Editor,
Policy makers in the US and other wealthy countries favor universal vaccination, but problems with the AstraZeneca vaccine have given some of them pause. They are now restricting its use to adults over 55 or 60 who are more likely to be at truly high risk from the disease and therefore justify the risks of vaccine adverse effects. (Dyer, BMJ 2021;373:n883, April 1) Some of us think that all Covid-19 vaccines should be given only to high-risk individuals and allow the other ~80% of the population that is low-risk to acquire broad and lasting natural immunity.
In the US official policy overwhelmingly favors universal vaccination as the only way to end the pandemic, with the implication that annual vaccinations will be necessary thereafter. What is the scientific basis of this policy? What is the basis for statements in daily newspapers and some medical journals that vaccine immunity will be more durable than immunity from natural infection? Long experience has taught us that natural infection generally produces broader and more lasting immunity than a vaccine against the target disease. Are human coronaviruses exceptions to this general rule? Are there comparative data showing that immunity from Covid-19 vaccines is broader and lasts longer? One reason influenza vaccines have never been shown to be lifesavers is that annual vaccination subverts broad and lasting individual protection from a natural infection and the population immunity against influenza variants that results. (Bodewes et al, Lancet Inf Dis 2009;9:784. J Virol 2011;85:11995) This partly accounts for the unfortunate history of influenza vaccines. (https://www.bmj.com/content/371/bmj.m4037/rr-3) Is this what we have to look forward to with universal Covid-19 vaccination?
Pfizer and Moderna vaccines are said to be 90% to 100% effective in preventing Covid-19 illness in interim reports after 6-8 weeks of follow-up. What will the numbers be in 6 months or a year? The limited evidence available indicates that natural infection is 80% to 95% effective in preventing reinfection for at least several months. (Hansen et al, Lancet 2021;397:1204, March 17. Abu-Raddad et al, Clin Infect Dis 2021, online 13 Dec 2020)
One measure of the protection of natural infection is the immune response, which is quite potent when compared with vaccine immunity. Unvaccinated individuals with a previous Covid-19 infection have anti-S titres at least equal to titres in vaccinated individuals with no previous infection, and a single vaccine dose increases their titres more than 140-fold to a level that is at least 10 times the level produced by two vaccine doses in uninfected individuals. (Manisty et al, Lancet 2021;397;1057, Feb 25) After a single vaccine dose previously infected individuals develop neutralizing antibody levels about 64 times higher and T-cell responses at least 10 times greater compared with responses in previously uninfected individuals. (Prendecki et al, Lancet 2021;397:1178, Feb 25)
We should assume that natural immunity will also provide better protection against Covid-19 variants than vaccine immunity. The vaccine-variant problem was recently dramatized by the observation that two doses of the AstraZeneca vaccine is only 10% effective against the B.1.351 variant while a single dose is 75% effective against the variants that preceded it. (Madhi et al, NEJM. online March 16, 2021) This is another reason to allow a large population of low-risk individuals to acquire natural immunity.
It has not been easy to dismiss the thrombotic events associated with the AstraZeneca vaccine (https://www.bmj.com/content/373/bmj.n883/rr-1), and they have provoked a re-think about risks and benefits. For example, 5000 people must be vaccinated with the Pfizer vaccine to prevent a single severe illness. (https://www.bmj.com/content/372/bmj.n567/rr) The remaining 4999 individuals derive no such benefit, but must reckon with an assortment of adverse events/effects now associated with the vaccines: flu-like illnesses occurring commonly during the week after vaccination, anaphylaxis, immune thrombocytopenia, serious thrombotic events, reactivation of autoimmune disease (reported to me by a correspondent), Bell’s palsy, and death.
Over the years there has been a consistent tendency for public health authorities to exaggerate the benefits of vaccines and ignore adverse effects, and a parallel tendency to exaggerate the risks of the target diseases. This has been particularly true of influenza and influenza vaccines. Without denying the seriousness of disease caused by Covid-19, I believe the same thing is now happening with the drive to universal Covid-19 vaccination. Why?
ALLAN S. CUNNINGHAM 4 April 2021