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Scientific findings suggest that autoimmunity may be triggered by vaccine adjuvants, of which aluminum compounds have been the most studied and the most widely used.<br>
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Vaccine and Thrombocytopenia Professor Osama El Safi 2022
Scientific findings suggest that autoimmunity may be triggered by vaccine adjuvants, of which aluminum compounds have been the most studied and the most widely used.
Adjuvants are molecules , which , in combination with antigens ,enhance immunological response. This enables an easier and more effective recognition of” non self” which in turn permits the triggering of adaptive and innate immune responses
A Adjuvant effect The term “adjuvant effect” refers to the co-administration of an antigen with a microbial specific factor to enhance an antigen - specific immune response in vivo. The microbial components of adjuvants activate APCs to produce pro-inflammatory cytokines (“non-specific” signal 2) and to up-regulate molecules essential for antigen presentation. These molecules include major histocompatibility complex (MHC) class II (antigen-specific signal 1) and B7-1/2. These innate immune events allow a more effective presentation to the adaptive immune system, resulting in an augmented activation and clonal expansion of T cells .
Mechanisms of adjuvanticity Adjuvants may exert their immune enhancing effects according to five immune functional activities: 1. Translocation of antigens to the lymph nodes where they can be recognized by T cells. 2. Antigen protection enabling longer exposure. 3. Enhanced local reaction at the injection site. 4. Induction of the release of inflammatory cytokines. 5. Interaction with PRRs, specifically TLRs .
ITP following vaccination Immune thrombocytopenia (ITP) is an autoimmune disorder in which autoantibodies inhibit platelet production and impair the circulating ones, leading to thrombocytopenia It is most commonly idiopathic, but it can also be found secondary to other conditions, such as infections (Cines et al., 2009). Most recently it has also been described following different types of vaccination. Considering the pathogenesis of autoimmune disorders following infections, vaccines could lead to ITP by molecular mimicry, epitope spreading, and polyclonal activation, especially in cases of attenuated virus stimulation (Guimarães et al., 2015; Kivity et al., 2009; Pordeus et al., 2008).
The term ‘mosaic of autoimmunity’ indicates that immune- mediated disorders can involve different sources, including genetics, environmental factors, and hormonal or immune defects (Shoenfeld and Isenberg, 1989). Together with other environmental factors, such as chronic silicone exposure (Watad et al., 2018; Watad et al., 2019), aluminum is one of the triggers for the recently described ‘autoimmune/inflammatory syndrome induced by adjuvants’ (ASIA), which involves mild-to-severe reactions following exposure to different adjuvants (Perricone et al., 2013; Watad et al., 2017).
ITP has been described as one of these reactions (Tomljenovic and Shaw, s2015).Regardless of the mechanism through which artificial immuni causes ITP, it has been reported following vaccinations against various infectious agents, especially measles-mumps- rubella (MMR), but also Haemophilus influenza, hepatitis B virus (HBV), human papilloma virus (HPV), varicella-zoster, diphteria- tetanus-acellular pertussis (DTap), polio, and pneumococcus (Cines et al., 2009; Perricone et al., 2014; Garbe et al., 2012; Jin et al., 2013; Genovese et al., 2018). A French study that evaluated drug-induced ITP found that around 45% of the cases were post-vaaccinal (Moulis et al., 2012).
Effect of Measles Vaccine on The Platelet Count Oski. N Engl J Med. 1966;275:352.
ITP and the Measles, Mumps, Rubella (MMR) Vaccine • First controlled study found increased risk of ITP 15-35 days after vaccination • A 2001 study in the UK linked hospital admission data to regional immunization records • Absolute risk of ITP within 6 weeks of MMR vaccine: 1 in 22,300 doses • Vaccine-associated cases tended to have a higher platelet count, shorter duration of admission, and higher rate of remission • Cases of ITP after MMR immunization were initially reported in the 1980s-1990s ITP episodes by interval from MMR vaccination Slide credit: clinicaloptions.com Miller. Arch Dis Child. 2001;84:227.
Vaccines and Development of New-Onset ITP • Vaccines, like infections, are hypothesized to lead to ITP by molecular mimicry, epitope spreading, and polyclonal activation, and also in relationship to adjuvants • Only vaccine with a reliable relationship to ITP is MMR1,2,4,5 • Lower incidence of ITP than following natural measles, mumps, or rubella infection • Lower incidence (1:40,000 doses) than non-vaccine-related ITP • >80% of patients recover within 2-6 months, typically within several weeks • Childhood ITP has been reported after almost every other vaccine but with a lower frequency and without a proven association • Study of 198 adult ITP cases and 878 matched controls in France (2008-2011)3 • 33.3% cases received a vaccine within the 12 mo before ITP compared with 34.5% of controls • No prior proven association between virus vaccines and onset of adult ITP 1. O’Leary. Pediatrics 2012;129:248. 2. Black. Br J Clin Pharmacol. 2003;55:107. 3. Grimaldi-Bensouda. Blood. 2012;120:4938. 4. Di Pietranotonj. Cochrane Database Syst Rev. 2020;4:CD004407. 5. Cecinati. Hum VaccinImmunother. 2013;9:1158.
COVID-19 Vaccines and New ITP Diagnosis ITP is a diagnosis of exclusion, so it is difficult to be conclusive about association Must be differentiated from vaccine-induced thrombotic thrombocytopenia VAERS thrombocytopenia data (March 2021): 77 reports (Pfizer-BioNTech, n = 37; Moderna, n = 40)1 77% after 1st dose, 23% after 2nd dose Median platelet count of 3 x 109/L after a median of 8 days after vaccination Of those reported, ~90% of patients responded to first-line treatments Incidence of ~1 case per million doses is lower than idiopathic ITP AztraZeneca ChAdOx1 vaccine associated with 1.13 cases of ITP per 100,000 doses in Scottish population2 The relationship between SARS-CoV2 vaccines and the development of new ITP is not clear. If there is a causative relationship, the incidence is very rare. The risk appears to be far less than the risk of ITP associated with COVID-19 infection.3 1. Lee. Blood 2021;Sep 29:[Epub]. 2. Simpson. Nat Med. 2021;27:1290. 3. Bhattacharjee. SN Compr Clin Med. 2020;Sep 19:1.
COVID-19 vaccines and Pre-existing ITP diagnosis • SARS-CoV-2 vaccines are generally safe in patients with pre-existing ITP • Multiple reports over the last year of cases and case cohorts • Thrombocytopenia exacerbations occur in ~10%-20% of patients with each dose, including those on and off treatment Platelet count change from baseline after SARS-CoV-2 vaccination1 1. Lee. Blood. 2021;Sep 29:[Epub]. 2. Kuter. Brit J Haematol. 2021;195:365.
COVID-19 Vaccines and Preexisting ITP Diagnosis Platelet Count Change From Baseline After SARS-CoV-2 Vaccination Symptoms Platelets fell 6/52 (12%) No symptoms No change in platelet counts 38/52 (73%) • Exacerbation of ITP • Generally responds to rescue treatment and/or increase in current treatment • May be more likely in those with more refractory ITP (splenectomy, multiple prior treatments) No symptoms No platelet counts 8/52 (15%) 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 Patient Number Second Dose First Dose 800 500 700 450 600 500 400 400 400 350 350 300 300 250 Platelet Count (x109/L) Platelet Count (x109/L) 250 200 200 150 150 100 100 50 50 0 0 Last Value in the Mo Before Vaccination Day 7 ± 3 After First Vaccination Last Value Between Vaccinations Day 7 ± 3 After Second Vaccination Crickx. Br J Haematol. 2021;[Epub]. Kuter. Br J Haematol. 2021;195:365.
Is It Safe to Vaccinate Patients with ITP? • Study of MMR vaccine after ITP diagnosis in children showed no vaccine-associated recurrence1 • Epidemiologic studies of 2nd dose of MMR vaccine does not show association with timing of ITP2 • However, transient worsened thrombocytopenia in the setting of infections or vaccines is well known Incidence of ITP Consider a pre-vaccination platelet count and then a platelet count 1 week after each vaccine. Guidance with 2nd vaccine if worsened thrombocytopenia with the first is not clear. 1. France. Pediatrics. 2008;121:e687. 2. Stowe. Arch Dis Child. 2008;93:182.
The recognition of the rare but serious and potentially lethal complication of vaccine induced thrombotic thrombocytopenia (VITT) brought concern regarding the safety of COVID-19 vaccines and led to the reconsideration of vaccination strategies in many countries. Following the description of VITT among recipients of adenoviral vector ChAdOx1 vaccine, a review of similar cases after Ad26.COV2⋅S vaccination gave rise to the question whether this entity may constitute a potential class effect of all adenoviral vector vaccines.
Potential mechanisms inducing VITT Since this infrequent complication has to date not been observed among other vaccine types, the question arose whether VITT/TTS observed across two independent adenoviral vector vaccines may represent a side effect unique to this vaccine category. Vaccines of this type use recombinant, non-replicative adenoviruses which act as shells for the carriage of the DNA strand that codes for the SARS-CoV-2 spike protein, which is necessary for its pathogenicity.
Upon intramuscular administration, recombinant viruses : 1-enter local cells expressing, among others, the Coxsackie-adenovirus receptor (CAR) via clathrin-mediated endocytosis, 2-the carried episomal DNA enters the nucleus, is transcribed into mRNA coding for viral spike protein 3-and is the translated in the endoplasmic reticulum. 4-A number of mechanisms implicating adenoviral vectors and/or other vaccine ingredients as triggers of Prothrombotic states have been proposed:
The striking clinical and laboratory similarities between VITT/TTS and HIT may imply that a similar autoimmune mechanism may underlie both conditions. • In heparin induced thrombocytopenia (HIT), the pathogenic autoantibodies target PF4 complexes with heparin, which is chemically a polyanion itself. • A syndrome similar to HIT without prior heparin therapy(termed autoimmune HIT - aHIT) can follow the exposure to a variety of other large polyanions such as hypersulfated chondroitin sulfate, DNA or RNA and bacterial wall components.
In any case, the PF4-polyanion-autoantibody complexes activates platelets through their Fcγ-receptors resulting in an increased risk of thrombosis. In the case of VITT/TTS, the adenoviral DNA content or other currently unaccounted for polyanionic vaccine contents could bind to PF4, and hence induce autoantibody production and subsequent platelet activation, which would essentially render VITT/TTS a subtype of aHIT. This mechanism was supported by Greinacher et al. in one of the original case series of ChAdOx1 recipients . In favor of this mechanism is the universal demonstration of circulating PF4/Polyanion autoantibodies as well as the predominance of young females among cases, a population which is most susceptible to autoimmunity. Platelets also express CAR ,so it can be hypothesized that megakaryocytes, their nucleated precursors may be susceptible to recombinant adenovirus infection. A subsequent SARS-CoV-2 spike protein expression could render platelets primary antibody targets or enhance thromboxane A2 production .
3. Following intravenous administration, adenoviruses may bind to circulating platelets in a von Willebrand Factor- and P-selectin mediated fashion, causing their activation and sequestration in the reticuloendothelial system . Furthermore, injection through this route induces endothelium activation as indexed by increased VCAM-1 (vascular cell adhesion molecule 1) expression, which may further contribute to the establishment of a Prothrombotic milieu .
Although such phenomena are not expected after intramuscular administration, an intravenous injection of a smaller or larger volume of the vaccine solution cannot be definitely excluded in some cases, especially when administering the vaccines under immense time pressure conditions as is often the case in vaccination centers.
4. Apart from platelets, anti-PF4 antibodies may also bind to and activate various other cell types, such as neutrophils , monocytes (hence inducing the expression of tissue factor) , as well as endothelial cells , therefore further promoting thrombotic manifestations. 5. Greinacher et al. have proposed that the Ethylene diaminetetra- acetic acid (EDTA) contained in the vaccine preparation may increase local vascular permeability in the injection site and cause the systematic dissemination of vaccine components which interact with preformed natural antibody, inducing a serum sickness-like illness. This inflammatory state may act as a co-signal to augment the antibody production of anti PF4-antibody-producing B-cells .
Is VITT observed in all marketed adenovirus-vector vaccines? However, there are no sufficient safety data regarding other adenovirus-vector vaccines used in COVID-19 prevention in light also of concerns of Ad-5 replication .
