Vaccines simulate a specific infection and through a well developed process stimulate the adaptive immune system to create antibodies and killer cells to destroy the contents of the vaccination.
Once destroyed versions of these cells are left behind, inactive but with a memory of what that specific infection might look like if it ever entered the body in the future. They would be ready to destroy it even before a person feels ill.
That is it. It involves B cells and T cells and they are helped by something called cytokines. All in the adaptive immune system. No need for, nor mention, of complement for that process. So why should it be a topic for aHUS/cTMA patients?
Well under the process described above it cannot be done in isolation. Complement has a role. Something it performs quite naturally and something that helps with creating new immunity quicker and stronger.
Parts of complement in what is known as its Classical Pathway still do what they naturally do by putting markers on what the vaccine has put in the body so that the adaptive immunity spots it sooner and with a stronger response. The result of that is an earlier and stronger immunity. Complement also helps clear up the debris from the contents of the vaccine. Win-Win.
Vaccines do not have to make complement do it, it does it of its own accord. In low level unthreatening activation. Not a worry for aHUS.
But some vaccines do have contents which deliberately or unintentionally stimulate complement activation, sometimes beyond the low level activation level. Now that it is worry.
What are these contents? They are known as adjuvants. And if used , they are different substances in different types of vaccines. Vaccines for Shingles and RSV for example use them to make vaccines more effective, for example, in older people who have weaker immune systems. The adjuvants are very good for them. They can activate complement during the vaccine process up to an including C5a inflammation response as well as sC5b-9 membrane attack complex.
The most commonly deployed COVID vaccines from Pfizer and Moderna do not have adjuvants. But these vaccines use mRNA technology. In these vaccines a set of instructions is inserted in the body which once activated create a version of a COVID virus. It is this version of a COVID virus that the adaptive immune system creates antibodies and killer cells for to attack it and produce cells which will remember the virus if there is ever an actual COVID infection in the future.
Although there are no adjuvants in them the mRNA instructions are rapped up in a substance known as LPNs , in doctors’ speak lipid nanoparticles. LPNs can and do act like adjuvants and stimulate complement activation which is helpful to the system creating immunity. Stronger and quicker because of complement signalling it to do so. Even in the inflammation process.
It is recognised that in some people it will lead to excessive inflammation caused by complement which will provoke a coagulation response which could end up as a thrombotic microangiopathy or TMA. Hence the concern.
The same vaccines can do the same for TTP too which is a TMA but it is not a complement mediated disease. So it is not that straightforward.
Something mentioned earlier, cytokines need to be brought up again.
Cytokines are the messengers to the adaptive immune system much like component C1 is in complement. It sends out signals about a “foreign body” to be attacked. Cytokines can cause inflammation. Control of cytokines can be lost and excessive inflammation can follow. Hyper cytokine inflammation is the dominant inflammatory response during a COVID infection particularly in the lungs and in severe cases. It can also dominate as a response to a vaccination. This too can result in a coagulation response with a possible TMA.
Even if cytokines are the predominant cause, it is possible for aHUS/cTMA to happen earlier, concurrently or even sequentially as part of an interaction of the two immune systems. Though aHUS/cTMA much rarely occurs.
The most common side effect of cytokine inflammation is myocarditis/ pericarditis which is still very rare and is often mild and resolvable. Even rarer is any TMA. Rarer still is any cTMA.
For context it is estimated that cTMA triggered by vaccination is a 1 in 50 million population event. The overall incidence rate of aHUS/cTMA is about 0.5 in a million. In the USA there are roughly 165 new incidents of cTMA each year so it is likely that maybe 5 or 6 of them are triggered by vaccinations some if not all of those vaccines could be for COVID.
If vaccine associated TMA is treated with a complement inhibitor and it is resolved then complement is a factor or cofactor. But if not resolved then cytokines are at play and anti-inflammatory treatment is needed. Or maybe both inhibitors and anti-inflammatories are needed as monotherapy is not sufficient.
So there are three TMA scenarios- a cTMA, a Vaccine associated TMA, or a cTMA secondary to Vaccine Associated TMA.
In current names they would be in turn Primary aHUS, Not aHUS and Secondary aHUS
But COVID infection is also triggering cTMA as complement is seen as bigger player in COVID disease course than was initially thought.
Whilst precise numbers are not available there have been 750m to 3 billion COVID infection cases. If unregulated complement had been involved in these cases aHUS/cTMA would be one of the most common diseases in the world rather than one of the rarest. Similarly if a complement inhibitor had been THE treatment for COVID then it would no longer justify a rare disease price status. Alexion’s production capacity would be overwhelmed. Governments would have stepped in to raise supply significantly as a national emergency.
But it has not and to our knowledge the prevalence of aHUS/cTMA has not significantly risen.
This would be the case for vaccinations too. Again no precise figures but globally there have been around 14 billions vaccinations performed. Yet aHUS /cTMA remains an ultra rare disease.
This is the context within which a discussion about vaccination risks is taking place. But the key people who are affected are those with a known predisposition whether in untreated remission or have not been triggered yet.
They too are divided into those who could access a complement inhibitor if onsetting so can mitigate the risk, and those who cannot.
For those in the general population who might be impacted, it does not feature in their decision making , except for the noise by anti-vaxxers generally citing the myocarditis/pericarditis side effect rather than the very rare cTMA. If they were to read the information leaflet which comes in the carton for both Pfizer and Moderna leaflets, they would find side effects listed as below.
There is no mention of the very rare thrombotic microangiopathy TMA. Though allergic reactions are mentioned which is a serious inflammatory system response ( cytokines or C5a at play ?) .
But should there be?
SIDE EFFECTS
Common/Very Common Side Effects (Often >10% in Trials)Injection site reactions (very common):
- Pain, tenderness, swelling, redness (erythema).
- Sometimes arm pain or itching.
Systemic/general (very common or common):
- Tiredness/fatigue.
- Headache.
- Muscle pain (myalgia).
- Joint pain (arthralgia).
- Chills.
- Fever/pyrexia.
- Nausea, vomiting.
- Feeling unwell/malaise.
- Swollen/tender lymph nodes (axillary/undearm, more after booster). products.modernatx.com
In children (additional or more prominent): Irritability/crying, drowsiness/sleepiness, decreased appetite, etc.
Less Common/Uncommon/Rare
- Diarrhea.
- Decreased appetite.
- Dizziness.
- Insomnia.
- Excessive sweating/night sweats.
- Rash (general or at injection site; delayed rashes possible ~9-11 days post-injection for Moderna in some cases).
- Injection site itching or hives.
Rare: Temporary one-sided facial drooping (Bell’s palsy).
Serious/Rare but Highlighted Risks Both vaccines explicitly mention in recipient information:
- Severe allergic reactions (anaphylaxis or hypersensitivity): Difficulty breathing, swelling of face/throat, fast heartbeat, bad rash, dizziness/weakness. Usually within minutes to 1 hour.
- Myocarditis (heart muscle inflammation) and pericarditis (lining around heart): Chest pain, shortness of breath, fast/irregular heartbeat/palpitations. Most reported in adolescent/young adult males (especially after dose 2), within first week (often days). Most cases mild with recovery, but monitoring advised. labeling.
- Fainting (syncope) associated with injection (common with many vaccines).
Article No: 802
