article continued…

Should My TBD Patient Get the COVID-19 Vaccine?

In light of all of the above, a valid question to pose is, should a patient who has TBDs get one of the COVID-19 vaccines? After all, patients with intact immunity generally do have reactions to the vaccine, especially after the second dose, and strong reactions reportedly occur in 30%. These can consist of fever, chills, weakness, fatigue, head and body aches and injection site soreness. It has been observed that TBD patients who are currently symptomatic may react more strongly to the vaccine and in theory, could even get ADE (“antibody-dependent enhancement”)—a cytokine storm from stimulating an already activated immune system. Before we can answer this, we first have to consider the properties of the individual vaccines for COVID-19:

• mRNA vaccines induce host cells to directly create spike proteins, a process that occurs in the cytoplasm, similar to a natural SARS CoV-2 infection.
• Human adenovirus with coronavirus sequences added: these are genetically modified DNA viruses engineered to induce host cells to create spike proteins. This process begins in the cell nucleus and then moves to the cytoplasm. Adenoviruses used to vector this include adenovirus type 5 and 26. Problem is, if we have immunity to these adenoviruses then our defenses can deactivate the vaccine before it gets a chance to work. This is especially a concern with the two-dose regimens many of these require—second dose may not be as protective as hoped.
• Chimpanzee adenovirus—same mechanism as above. A chimpanzee adenovirus was chosen because of the low likelihood that humans have immunity to this and therefore our defenses are less likely to deactivate the vaccine.
• Attenuated SARS CoV-2 coronavirus: these are made from the intact virus that has been deactivated, so immunity can develop without causing an infection in the process.
• Peptide vaccine: here, the method is to insert SARS CoV-2 genes into a virus that then infects arthropod cells (a moth!!) which then produce spike-forming proteins. These proteins are assembled into spikes and are injected along with an adjuvant.

The vaccine table (below/Table 1) is for general reference.

Table 1. COVID-19 Vaccines. Note the statistics on efficacy are not comparable among individual vaccine types because the way efficacy is measured is not standardized.

Vaccine type	Efficacy	Antigen	Refrig	Adjuvant	Doses
mRNA Moderna	94%	Spike	frzr	No	2
mRNA Pfizer	95%	Spike	-97 frzr	No	2
J&J	66-85%	Ad 26	refrig	No	1
Adenovirus vector AZ/U Oxford	70-90%	Chimpanzee adenovirus	refrig		2
Inactivated CV (Sinovac, Coronavac)	50%?	Whole CV	refrig	Yes	2
Inactivated CV (Sinopharm)	50%?	Whole CV	?	Yes	2
Sputnik (Gamaleya)	91%	Ad 5&26	frz	No*	2
Covaxin	?	Whole CV: Spike, RBD, Nucleocapsid protein	frz	Chemosorbed imidazoquinoline onto aluminum hydroxide gel	2
CanSino	?	Ad 5	refrig	Yes	1
nanoparticles (Novavax)	?	Spike made on moth cells	refrig	Soapbark tree	2

Antibody-Dependent Enhancement (ADE)

ADE is a cytokine storm induced by an extreme immune reaction to antigens, and this is more likely to occur if the patient had been previously sensitized to these antigens.

Mechanism of ADE in COVID-19. With infection, neutralizing and non-neutralizing antibodies form. Neutralizing antibodies inhibit the infection and prevent the spike protein from binding to the ACE-2 receptor, thereby halting the spread of the infection. The non-neutralizing antibodies do not inhibit the spike protein, and when complexed with viral antigen will bind to macrophage receptors and allow viral entry independent of ACE-2 receptors. The macrophages activate and initiate an inflammatory cascade, and the uninhibited viral entry allows it to propagate. It has been proposed that an excess of non-neutralizing antibodies is what is responsible for ADE to occur (theory, not proven).

Can COVID-19 vaccines cause ADE? If the vaccine has predominantly spike protein as the antigen, then it is unlikely that ADE will result (mRNA vaccines and the adenovirus-vectored ones). However, vaccines made from whole, attenuated coronaviruses may be more of a risk because there are antigens in addition to the spike that we may react to. Vaccines that contain adjuvants are a theoretical concern because adjuvants are nonspecific, non-neutralizing immune stimulants.

Because some propose that previous exposure to this or a similar antigen can cause immune overstimulation, then ADE after vaccination may be more likely if there was a significant coronavirus infection in the past. This is why I and others advocate antibody and/or ELISPOT testing for the virus before giving the injection. The risk of ADE may also be increased after the second dose of vaccine or if exposed to SARS CoV-2 within 10-14 days after vaccination. All of this is conjecture only; there has not been enough experience with any of these vaccines to know if these are real risks.

TBD Patients and COVID-19 Vaccination Recommendations

• Consider testing for SARS CoV-2 antibodies by immunoblot and T-cell responsiveness by ELISPOT prior to vaccination to uncover past infection that may have been missed. If immunity is present, then defer the vaccine and retest in four to six weeks.
• Always try to prepare your patient prior to vaccination by initiating and then continuing all the needed supportive measures.
• Do not vaccinate during a TBD symptom flare—likewise may have to hold TBD treatment well before vaccination to calm a Herxheimer.
• mRNA vaccines may be safer than whole-coronavirus vaccines.
• With couples, stagger vaccination schedules.
• Avoid immunosuppression as it may weaken vaccine-induced immunity.
• If there is a strong reaction to the first dose, then you may elect to postpone the second dose and then follow SARS CoV-2 immunity to judge if and when to give the second dose.

Conclusions

Many of us are now dealing with two complex conditions—TBDs and COVID-19. They may be difficult to differentiate in certain circumstances and both pose challenges for patient management. Now, however, better testing for TBDs and for SARS CoV-2 can be extremely helpful in guiding our patient management.

COVID-19 vaccination, while beneficial, can be difficult to tolerate in the TBD patient and require careful management pre- and post-dose. However, the risk of a short-lived vaccine reaction may far outweigh the risk of a full-blown COVID-19 infection in these patients. If the vaccine reaction was strong, one can only imagine what the real thing could be like. Finally, I urge everyone to keep track of their data and share it so we all can learn from each other.

Please stay safe!