CME INDIA Presentation by Dr S K Gupta, MBBS MD(Med), CFM (France), Senior Consultant Physician, Max Hospital, Delhi.

Does COVID vaccine cause Antibody Dependent Enhancement?

As the second wave is getting momentum, people rush to get vaccinated. Many co-morbidities pose challenge for vaccination and people want specific answers from physicians.

Rheumatoid Arthritis and Vaccination

Q. 55 yr Female patient took inj Plamumab 40 mg 15 days back and she is also taking Sazo 1000 mg BD, and   along with Etorocoxib.Kindly advise if she can go for Vaccination? If yes, then what blood test she should get done before vaccination?

Answer:

• She can go for vaccination safely and no modification in above treatment is warranted.
• Nor any delay or change in Schedule of vaccination is required. No Tests are required to be done for purpose of vaccination.
• Patients on HCQ, Intravenous Immune Globulin (IVIG) and Steroids less than 20mg of Prednisolone (or equivalent) can very safely take vaccine.
• Patients on Sulfasalizine Leflunomide, cyclophosphamide (oral), Azathioprine, and steroids (more than 20mg of Prednisone equivalent) can go for vaccine *safely. Try reducing the dose of Steroids to less than 20mg per day if disease activity permits.
• Patients taking Adalimumab the TNF blocking monoclonal antibody (Plamumab) can take vaccine safely. No change in timing of drug or vaccine warranted.
• Patients on Methotrexate and/or Jak inhibitors should stop the dose at least one week after each dose of vaccine.
• Patients of Rituximab should stop the therapy 4 weeks after each dose of Vaccine.

The COVID-19 vaccines are safe for people with Multiple Sclerosis (MS)

• None of the available vaccines contain live virus and the vaccines will not cause COVID-19.
• The vaccines are not likely to trigger an MS relapse or have any impact on long-term disease progression.
• The risk of getting COVID-19 far outweighs any risk of having an MS relapse from the vaccine. 
• Caution:
  • Any vaccine can cause side effects, including a fever. A fever can make MS symptoms worse temporarily, but they should return to prior levels after the fever is gone.
  • *Even if one has side effects, it’s important to get the second dose of the vaccine for it to be effective. 
• The vaccines are safe to use with MS medications.
• Continue disease modifying therapy (DMT) unless one is advised by MS healthcare provider to stop or delay it. Stopping some DMTs abruptly can cause severe increase in disability with new lesions on MRI.
• Based on data from previous studies of other vaccines and DMTs, getting the COVID-19 vaccine while on any DMT is safe.
• Some DMTs may make the vaccine less effective but it will still provide some protection. For those taking Kesimpta, Lemtrada, Ocrevus, or Rituxan— consider coordinating the timing of vaccine with the timing of DMT dose.
• Any preferred vaccine for those living with MS. – Any of the authorized vaccines is safe to get. There is no vaccine preference.
• Evidence on the impact of DMTs on COVID-19 severity – Interferons (Avonex, Betaseron, Extavia, Plegridy, Rebif) and glatiramer acetate (Copaxone) are unlikely to impact negatively on COVID-19 severity. There is some preliminary evidence that interferons may reduce the need for hospitalization due to COVID-19.
• The evidence available suggests that people with MS taking dimethyl fumarate (Tecfidera), diroximel fumarate (Vumerity), teriflunomide (Aubagio), fingolimod (Gilenya), natalizumab (Tysabri), ozanimod (Zeposia) and siponimod (Mayzent) do not have an increased risk of more severe COVID-19 symptoms.
• There is some evidence that therapies that target CD20 – ocrelizumab (Ocrevus) and rituximab (Rituxan)– may be linked to an increased chance of having a more severe form of COVID-19.
• However, these therapies should still be considered as an option for treating MS during the pandemic.
• People with MS who are taking them or ofatumumab (Kesimpta) that works in the same way, should be particularly vigilant regarding the advice here to reduce their risk of infection.
• More data on the use of alemtuzumab (Lemtrada) and cladribine (Mavenclad) during the COVID-19 pandemic are required to make any assessment of their safety. People with MS who are currently taking these therapies and are living in a community with a COVID-19 outbreak should discuss their current lymphocyte counts with their healthcare professional. If their counts are low, they should isolate as much as possible to reduce their risk.
• In case of Collagen Vascular Disorders American College of Rheumatology recommends stopping Rituximab and similar drugs 4 weeks after each dose of vaccinations.
• Recommendations on delaying second or further doses of alemtuzumab, cladribine, ocrelizumab and rituximab due to the COVID-19 outbreak differ between countries.
• Second dose of Vaccine – People who take these medications and are due for the next dose should consult their healthcare professional about the risks and benefits of postponing treatment.
• People are strongly encouraged not to stop treatment without the advice of their clinician.
• Special Note on Methyl prednisolone:
  • Use of methylprednisolone include.
  • Medrol 4mg (oral),
  • Depo-Medrol (METHYLPREDNISOLONE ACETATE 20mg in 1mL) I/M or IV 40 to 80 mg,
  • Solu-Medrol Intravenous methylprednisolone sodium succinate 1gm vial.
• Half-life of Methyl Prednisolone:
  • Mean elimination half-life ranges from 2.4 to 3.5 hours in normal healthy adults and appears to be independent of the route of administration hence all the drugs should get cleared within 13 to 20 hours. (Drug is metabolised in Liver so dose need not be adjusted in Renal patients) 
  • It takes approximately 5.5 times the elimination half-life for a medicine to be cleared from body which is (5.5 x 2.5 hours) 13.75 hours to (5.5 x 3.5 hours) 19.25 hours.
• Hence, the Vaccination should be planned in such a manner that immunosuppressive effects of steroid injection have little chance of interfering with development of Antibodies after a vaccine.
• Do not receive a “live” vaccine while using Methyl Prednisolone. Live vaccines include measles, mumps, rubella (MMR), rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

Covid-19 Vaccination in Epilepsy

1. No study to date has assessed the COVID-19 vaccine in patients with epilepsy.

2. Epilepsy does not increase the risk of contracting COVID-19. 

3. There is currently no evidence to suggest that epilepsy is specifically associated with a higher risk of side effects from a COVID-19 vaccine. There is no evidence that this vaccination results in worsening of the epilepsy, or brain injury.

4. For people with epilepsy, the risk of COVID-19 infection and potential complications far outweighs the risk of side effects from a COVID-19 vaccine.

5. Are people having Epilepsy At Higher Risk Of Side Effects of Vaccine?

There is no evidence that persons with epilepsy are at higher risk of side effects after vaccination. As with any vaccine, some persons may develop a fever which could lower their seizure threshold for the short term, and rarely could result in a break-through seizure.

6. Should people with Febrile Seizures Avoid Getting the COVID Vaccine?

Fever is a common side effect after getting a vaccine. And it may precipitate Seizure in some people with epilepsy.

The available data on safety still support vaccination. If someone has seizures triggered by fever, it may be good to talk to one’s health care provider to assess risk benefit. Pre emotive use of Paracetamol for 48 hours following vaccination could be helpful and may be considered on individual basis.

Further, it is recommended to receive the vaccine, at such as a location where medical staff are available with a Seizure Action Plan including rescue therapies.

COVID-19 Vaccination and Neuropathy especially Guillain Barre’ Syndrome.

• Anthony Fauci, MD in early December 2020 said, “that people who have had Guillain-Barré syndrome (GBS) should avoid the SARS-CoV-2 vaccines because they might trigger a recurrence of the disease”. He faced severe criticism from experts who presented with data on the contrary.
• Later in mid-January he set the record straight saying that he had misspoken. Dr Fauci finally said “I have a sense that people who develop any neurological complications will want to attribute it to the vaccines rather than to serendipity. People have very strong feelings about vaccines.”
• Source of the Trigger Evidence.
• Concerns about the risk of GBS in response to vaccines date back to 1976, when CDC has noted “there was a small increased risk of GBS after swine flu vaccination,”. Later It was found that risk of GBS was no more than 1 additional case per one lakh doses of vaccine.  Hence the CDC later corrected itself stating “Studies suggested that it is more likely that a person will get GBS after getting the flu than after vaccination.”
• On June 25, 2020, the New England Journal of Medicine published a letter from Italian physicians reporting five cases of GBS among more than 1000 patients admitted in 3 weeks period from Feb 2020 onwards.
• Counter Evidence.
• On December 14, however, the journal Brain published an epidemiological study which found that the incidence of GBS in the United Kingdom fell by 50% during the first wave of COVID-19 between March and May 20 compared to the same period during the past four years.
• During 2nd wave too, in October to December 2020, when UK saw up to 60,000 cases a day of COVID-19 the data for GBS remained entirely flat. If there had been a link of COVID-19 to GBS, one would expect the number of cases of GBS to increase during pandemic. There’s not even a bump.
• With billions of the world’s populations having been immunized one would have got thousands and thousands of cases of GBS associated with the vaccine if both had any correlation.  However, not more than one case of post vaccination GBS has been reported to CDC till date.
• CDC is of the view that no instances of GBS were seen during clinical trials of the vaccines, that no published studies suggest any cause for concern, and that neither the CDC nor FDA recommends against the vaccine due to GBS.
• Concerns that COVID vaccination might cause GBS in any significant numbers are therefore almost certainly unfounded. Scientists are studying the risk to benefit ratio of the vaccine in someone who previously developed Guillain Barré syndrome after a vaccination.

Antibody dependent enhancement post vaccination.

Dr Vivek Gupta, Surat shares a Forwarded message.

“With utmost care for over a year and two vaccines I became Covid positive. Last Friday mild throat pain and since Saturday very high fevers around 104 continued just dipped to 102 for two days. Tested antigen came Positive PCR test also confirmed 77. D Dimer 7472.Severe headache and High fever for continuous three days and above reports, I had no choice, got admitted at Hiranandani hospital. Now better on Remdesivir.”

Diagnosis: ADE. Antibody dependent enhancement post vaccination. One of the complications of vaccination.

CME INDIA Learning Points on ADE

• ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they are unable to prevent infection. Instead, these antibodies act as a “Trojan horse,” allowing the pathogen to get into cells and exacerbate the immune response.
• The risk of exacerbating COVID-19 severity via antibody-dependent enhancement (ADE) is a potential hurdle for antibody-based vaccines and therapeutics.
• ADE can increase the severity of multiple viral infections.
• ADE in respiratory infections is included in a broader category named enhanced respiratory disease (ERD). It also includes non-antibody-based mechanisms such as cytokine cascades and cell-mediated immunopathology.
• ADE caused by enhanced viral replication has been observed for other viruses that infect macrophages, including dengue virus and feline infectious peritonitis virus.
• If a person is infected by one serotype of dengue virus, they typically have mild disease and generate a protective immune response, including neutralizing antibodies, against that serotype. But, if that person is infected with a second serotype of dengue virus, the neutralizing antibodies generated from the first infection may bind to the virus and actually increase the virus’s ability to enter cells, resulting in ADE and causing a severe form of the disease, called dengue hemorrhagic fever.
• ADE has been observed in SARS, MERS and other human respiratory virus infections including RSV and measles.
• Existing evidence suggests that immune complex formation, complement deposition and local immune activation present the most likely ADE mechanisms in COVID-19 immunopathology.
• Clinical data has not yet fully established a role for ADE in human COVID-19 pathology.
•  Steps to reduce the risks of ADE from immunotherapies: – Induction or delivery of high doses of potent neutralizing antibodies, rather than lower concentrations of non-neutralizing antibodies that would be more likely to cause ADE.
• It will be crucial to evaluate animal and clinical datasets for signs of ADE, and to balance ADE-related safety risks against intervention efficacy if clinical ADE is observed.
• The important thing to know about antibodies is that we need to have Neutralising antibodies. Non-Neutralising or sub-Neutralising antibodies get attached to the virus and can direct this complex to the macrophages resulting in an Antibody Dependant Enhancement of CoViD 19 disease. This is being seen, though rarely, across the world. This phenomenon is seen with Dengue, measles and other syncytial viruses and is the cause of vaccination failure in Dengue. Should we get the levels of Neutralising Antibody in blood tested instead of the IgG against the S Protein. (Input-Dr H D Sharan, Ranchi)
• It is a possible hypothesis. We have witnessed in dengue infection where previous infection with one serotype led to generation of antibodies. This antibody will bind to second infection with different serotype. This complex will easily penetrate monocyte but will not be able to destroy it but rather replicate in it. So ultimately this type of patient will have more severe second infection, but this is not a universal phenomenon. Various other factors might be there to consider. But similarly, in COVID this is the basis of recent infection in vaccinated patient. (Input by Dr Vivek Gupta, Surat)
• Can the new COVID-19 vaccines cause ADE?

Neither COVID-19 disease nor the new COVID-19 vaccines have shown evidence of causing ADE. People infected with SARS-CoV-2, the virus that causes COVID-19, have not been likely to develop ADE upon repeat exposure. This is true of other coronaviruses as well. Likewise, studies of vaccines in the laboratory with animals or in the clinical trials in people have not found evidence of ADE.

Reference: www.chop.edu/centers-programs/vaccine-education-center/vaccine-safety/antibody-dependent-enhancement-and-vaccines

CME INDIA Tail Piece

Dr Dibeyendu Dey, DM, Haematology:

• So, for vaccine induced ITP, IVIG is drug of choice. Should be given earliest to nullify vaccine antibody binding to platelet.

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